A-arylation of malonates

Oh and coworkers reported a room temperature arylation of a-substituted malonates with NaH in DMF in 1999 [183]. These conditions were recently applied in the chemoselective arylation of a cychc p-ketoester with an unsymmetric, boron-substituted diaryliodonium salt, leading to a product with a suitable handle for further functionalizations [82]. Olofsson and coworkers performed a detailed chemoselectivity investigation with unsymmetric iodonium salts in the a-arylation of malonates, which resulted in the discovery of an anti ort/io-effect and the conclusion that both mesityl and anisyl moieties are suitable dummy groups in these reactions [27]. This fact was utilized by the group of Shibata, who developed a pentafluorophenylation of cyclic p-ketoesters with unsymmetric TRIP salts under mild conditions (Scheme 14a) [81]. 

Zeolites are very useful catalysts for a large variety of reactions, from acid to base and redox catalysis [27]. Hutchings et al. reported that bis(oxazoline)-modified Cu (II)-HY catalysts are effective for asymmetric carbonyl- and imino-ene reactions and aziridination of styrene [28, 29]. Recently Djakovitch and Kohler [30-34] found that Pd(II)-NaY zeolite activates aryl halides towards Heck olefination, a-arylation of malonate, and amination reactions. It is well known that alkali-exchanged faujasite zeolites are solid base catalysts [35]. Owing to the usefulness of zeolites in organic chemistry, and our interest, we recently reported the use of modified alkali-exchanged zeolite Y, NaY zeolite [36] with electron rich copper catalyst in the Y-arylation of nitrogen heterocycles with aryl halides to afford A -arylheterocycles in excellent yields under mild conditions without the use of any additive. 

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

As the last example of C-C bond-formation reactions catalyzed by alkaline earth hydroxides, we mention the recently reported a-arylation of diethyl malonate in the presence of a palladium catalyst and a base in a separate phase 299). The arylation of carbonyl compounds is a carbon-carbon coupling reaction between an aryl halide and an enolate, which is usually catalyzed by palladium salts in the presence of an appropriate base (300,301). The arylation of diethyl malonate with bromobenzene (Scheme 48) was performed with tetrachloropalladate as the... 

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)... 

Beare, N. A. Hartwig, J. F. Palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl- and ferro-cenyldialkylphosphine ligands. J. Org. Chem. 2002, 67, 541-555. 

Arylations. Arylation of malonic esters is achieved in good yields. The less electron-rich aryl group is transferred from unsymmetrical iodonium salts. A-Arylation of amines, amides, and lactams is under catalysis by Cul, whereas pyrimidinones undergo A-arylation using t-BuOK as base (no copper salt).- ... 

Recently, the limitations of the intermolecular reaction have been significantly mitigated [19-25]. Use of sterically bulky and electron-rich phosphines as ligands, typically P(t-Bu)3, allows the arylation of malonates as well as cyanoac-etates even with aryl chlorides (Eqs. 2 and 3) [22]. The reaction of malonates at a somewhat elevated temperature affords arylacetates accompanied by dealkoxycarbonylation (Eq. 4) [26,27]. 

Enolate Arylation Reactions. The direct coupling of aryl halides with enolates (or enolate equivalents) of ketones, esters, and amides is now well established. Malonic esters, cyanoacetates, and malononitrile can be arylated upon treatment with aryl halides in the presence of Pd(dba)2 and electron-rich phosphines or N-heterocyclic carbenes. Carbene ligands have also proven effective in promoting the a-arylation of protected amino acids. As a caveat to the use of Pd(dba)2, the arylation of azlactones in the presence of this palladium source and phosphines was less efficient than that with Pd(OAc)2. The dba ligands were found to react with azlactone substrates to form catalytically inactive palladium complexes. Diastereoselective enolate arylation has been achieved through the use of chiral auxiliaries appended to preformed enol silyl ethers (eq 23). The role of the zinc additive is not clear, however, it appears that discrete zinc enolates are not involved. 

A variety of bases have been used in the palladium-catalyzed a-arylation of carbonyl derivatives. The pKa of the carbonyl moiety determines the choice of the base. The preferred bases for the a-arylation with ester derivatives are either NaHMDS (r-butyl propionate) or LiHMDS (f-butyl acetate) as KHMDS was reported to lead to lower yield because of competing hydrodehalo-genation. More sensitive substrates such as a-imino esters, malonates, or cyanoesters required the use of a milder base, as decomposition was observed with HMDS bases. 

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]. 

Di- -butyl malonate can be arylated with electron-rich aryl chlorides using NaH and P(r-Bu)3 [11], The arylation suffers steric effects, and no arylation takes place with diethyl methylmalonate (9). Thus, diethyl methylphenylmalonate (10) can be prepared via arylation of malonate to give 11, followed by methylation as a one-pot reaction. When the arylation of diethyl malonate is carried out at 120 "C, phenylacetate (12) is obtained as a one-pot reaction product [12],... 

Other C-arylation reactions have been accomphshed with vinylogues of P dicarbonyls [93], malonic acid derivatives [94], a-cyano esters and malonitriles [95]. The a-arylation of ketone enolates/enamines and nitroalkanes has also been achieved [96-98]. 

Formal a-diarylmethylation of malonates was achieved through the development of a 1,6-selective conjugate addition-aromatization sequence with para-quinone methides as vinylogous electrophiles (Scheme 4) [8]. The driving force toward aromatization would make nucleophilic addition to the 8-position more thermodynamically favorable than addition to the p-position. Under solid-liquid biphasic conditions, the A-spiro chiral ammonium salt 5 appeared to be the most active and selective promoter. The electronic character of the aryl ester substituents on the malonate was linked to the stereochemical outcome, and introduction of a para-halophenyl group led to a significant decrease in the enantioselectivity. Based... 

Copper-catalyzed arylation of malonates [385] and other activated methylene compounds (malononitrile, ethyl cyanoacetate) [386] have also been reported. It is likely that the catalyticaUy active species is a Cu(I) enolate. 

Pd complexes catalyze the arylation of ester enolates generated in situ in the presence of a base (Buchwald, Hartwig, Scheme 19.30b) [35]. Arylation of malonates proceeds under similar... 

The synthesis of a-aryl activated derivatives has been approached via a Pd-catalyzed reaction. The enolate form of the activated nucleophile may act as a transmetallating agent, which may, therefore, react with a Pd intermediate resulting from the oxidative addition of aryl halides. Arylation of di-teri-butyl malonate was described in the presence of Pd(dba)2 catalyst the reaction also was possible with dimer 1 (eq 86). Aryl bromides and ethyl cyanoacetate also can participate in such reactions. Other ligands than P(f-Bu)3 were efficient for these couplings. The bicyclic triaminophosphine, P(i-BuNCH2CH2)3N, served as a versatile ligand for the Pd-catalyzed a-arylation of nitriles with aryl bromides. 

Figure 6.103 CuBr-catalyzed a-arylation of [2- C]malonates with iodopyridines...

No intennolecular reaction of malonate or /3-keto esters with halides has been reported, but the intramolecular reaction of /3-diketones such as 790 and malonates proceeds smoothly[652,653]. Even the simple ketone 791 can be arylated or alkenylated intramolecularly. In this reaction, slow addition of a base is important to prevent alkyne formation from the vinyl iodide by elim-ination[654]. 

Aryl lead tncarboxylates have been shown to be intermediates in two new routes to phenols, and to have considerable potential as reagents for the C-arylation of carbon acids which are more acidic than diethyl malonate. A... 

When an aromatic ring is treated with diethyl oxomalonate, (Et00C)2C=0, the product is an arylmalonic acid derivative, ArC(OH)(COOEt)2, which can be converted to an arylmalonic acid, ArCH(COOEt)2. This is therefore a way of applying the malonic ester synthesis (10-104) to an aryl group (see also 13-12). Of course, the opposite mechanism applies here The aryl species is the nucleophile. 

Palladium-Catalyzed Arylation of Enolates. Very substantial progress has been made in the use of Pd-catalyzed cross coupling for arylation of enolates and enolate equivalents. This reaction provides an important method for arylation of enolates, which is normally a difficult transformation to accomplish.171 A number of phosphine ligands have been found to promote these reactions. Bulky trialkyl phosphines such as /n. v-(/-butyl)phosphinc with a catalytic amount of Pd(OAc)2 results in phenylation of the enolates of aromatic ketones and diethyl malonate.172... 

Although most of the methods for the arylation of enolizable compounds so far developed rely on special phosphine ligands, there is a report of an unusually mild and efficient phosphine-free procedure for the arylation of diethyl malonate, the key to success of which is announced to be the use of a heterogeneous base. In this procedure all three halobenzenes, including PhCl, showed practically identical reactivity (49).198... 

Results Obtained in the Arylation of Diethyl Malonate with Bromobenzene Catalyzed by Na2PdCl4 and Various Solid Bases in a Batch Reactor (299)... 

The major advantages of this procedure over the enol sulfonate procedure lie in the availability of diethyl 2-chloro-2-cyclopropylethene-l,l-dicarboxylate from the corresponding acylmalonate and phosphorus oxychloride, and the fast, homogeneous, decarboxyl ative elimination reaction of the triethylamine salt of the half-ester in dry organic solvents. The conditions described here, with slight modifications (overnight treatment), have been used for a variety of g-chloro alkyl idene/aryl idene malonates as shown in Table I. 

Heating of a mixture of 2-phenyl-1,4-naphthoquinone (1 eq.) with dimethyl malonate (4 eq.) and manganese(III) acetate (6 eq.) in acetic acid at 80°C for 16 hours gives 1 in 76% yield, and this has been shown to be a general type of reaction for a variety of 2-aryl-l,4-naphthoquinones. 

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