Organic Chemistry Portal
Organic Chemistry Highlights

Monday, November 25, 2004
M. Manuel B. Marques
REQUIMTE - FCT - New University of Lisbon

Palladium-catalyzed alpha-Arylation of Esters, Ketones, Amides and Imides

One of the most challenging problems in organic synthesis is the formation of a C-C bond between an aromatic carbon and the carbon alpha to a carbonyl group. Recently, a significant effort has been devoted to improving and establishing palladium catalysis methodology as an efficient route to prepare many biologically active carbonyl compounds. In a recent review (Angew. Chem. Int. Ed. 2002, 41, 6, 953-956. DOI: 10.1002/1521-3773(20020315)41:6%3c953::AID-ANIE953%3e3.0.CO;2-9) , Lloyd-Jones summarized three methods developed for Ar-Cα bond formation via the palladium catalyzed arylation of ester enolates (Scheme 1).

Scheme 1 - Proposed Pd-catalyzed routes to α-arylated esters 1. Hartwig's and Buchwald's arylation routes proceed via trapping of the Ar-Pd intermediate 2 (X=Br, Cl) by an alkali metal enolate (M=Na, Li). Gooßen's route involves arylative transmetallation of a palladium enolate (4, X=Br) with 3 (M=B(OR)2).

The Hartwig, Buchwald and Gooßen groups have published new methods for the α-arylation of esters. The aim of this Highlight is to focus on the improvements to these methods that have been reported recently, and their application to esters, ketones and amides.

I. Palladium-Catalyzed alpha-Arylation of Esters

Hartwig and co-workers (J. Org. Chem. 2002, 67, 541-555. DOI: 10.1021/jo016226h) reported a procedure for the palladium-catalyzed arylation of malonates and cyanoesters using sterically hindered trialkyl- and ferrocenyldialkylphosphine ligands, as summarized in Table 1.

The use of these ligands proved to be very effective in the reactions of several malonates and cyanoacetates with both electron-rich and electron-poor aryl chlorides and bromides. These hindered ligands both accelerate reductive elimination and promote oxidative addition. The use of these ligands also solves the problem of the electronic properties of the carbonyl substrate sometimes being disadvantageous for the reaction.

Scheme 2 - Reaction of zinc enolates with bromoarenes that contain various reactive functional groups.

The basic reaction conditions present in the alkali metal enolate synthetic methodology limit its use, since functional groups like cyano, nitro, carboxyl and keto are reactive toward base. In addition, coupling at more hindered enolizable positions was not possible, and the basic conditions also limited the stereocontrol. The search for more neutral conditions led the Hartwig group (J. Am. Chem. Soc. 2003, 125, 11176-11177. DOI: 10.1021/ja036792p) to develop two procedures for a palladium-catalyzed α-arylation. The first one depends on the use of zinc enolates in combination with hindered catalysts like 5 (Q-phos) and the reactive dimeric complex {[P(t-Bu)3]PdBr2} (Scheme 2).

The Hartwig study concentrated on aryl bromides, which do not react under alkali metal enolate conditions. The catalyst with Q-phos provided a more general procedure. Coupling of aryl bromides with zinc enolates occurred at room temperature in high yield (Scheme 2), and no diarylation product was detected in the reaction of the zinc enolates of acetate (R=H) or propionate (R=Me).

The second process consisted of the reaction of silyl ketene acetals with bromoarenes, using zinc fluoride as a co-catalyst (Scheme 3).

Scheme 3 - Palladium-catalyzed coupling of bromoarenes with silyl ketene acetals

This approach avoids the use of toxic tin additives as well as the excess copper halide. The process has the advantage of the enolate being prepared directly from the ester, so that higher functional group tolerance and high yield result from the less basic, milder conditions employed (Scheme 3). The rate of transmetallation of the silyl enolate is improved by using this method.

Recently, the same group reported a more general procedure for the palladium-catalyzed arylation of trimethylsilyl ketene acetals in the presence of the additives ZnF2 or Zn(O-t-Bu)2(J. Am. Chem. Soc. 2004, 126, 5182-5191. DOI: 10.1021/ja031544e) (Scheme 4).

Scheme 4 - Arylation of trimethylsilyl ketene acetals in the presence of zinc additives

Reactions carried out in the absence of additives gave no products. Reactions carried out with 0.5 or 0.25 equiv of ZnF2 in DMF gave quantitative reaction - ZnF2 acts as a cocatalyst. Several aryl bromides and chlorides were tested (e.g, p-O2NPh, p-MeO2CPh, m-NCPh, p-O2NPh) in the presence of Pd(dba)2, P(t-Bu)3 and 0.5 equiv of ZnF2. The results showed that high yields can be obtained with a high tolerance of functional groups not observed in the coupling conditions of alkali metal enolates. This method provides a catalytic route to a wide variety of esters derivatives as will be showed below.

II. Palladium-catalyzed alpha-Arylation of Ketones

The Hartwig group reported a simple and highly active palladium catalyst system for the arylation of ketones, similar to the one described above for malonates (J. Am. Chem. Soc. 1999, 121, 1473-1478. DOI: 10.1021/ja983378u) (Scheme 5).

Scheme 5 - The reaction of ketones with arenes in the presence of sterically hindered phosphine ligands.

These conditions led to rapid reaction rates for aryl chlorides and bromides, and in many cases reaction occurred at room temperature. The yields varied from 69% (m-MeOPhCl, R1=Me, R2=i-Pr, 2% Pd(OAc2), P(t-Bu)3, 70 ºC, 12 h) to 99% (PhBr, R1=Me, R2=Ph, 2% Pd(dba)2, 7, 25 ºC, 2 h).

With catalyst 7(DtBPF), clean reactions with chloroarenes were only observed at 70 ºC, and ketones did not react with aryl tosylates when 7 was the catalyst, but good results were obtained with 8 (5 mol%). The reaction of ketones with alkylphosphine ligands, such as P(t-Bu)3, resulted in faster rates and good yields.

The Hartwig group supplemented their results with some mechanistic studies, and advanced the following conclusions: monophosphine ligands can activate aryl chlorides under mild conditions; reductive elimination takes place faster than β-hydrogen elimination with palladium enolates coordinated by monophosphines; the selectivity for the less hindered side of a dialkyl ketone is proposed to derive from chelation, where palladium complexes of monophosphines and bidentate phosphines act as catalysts.

More recently, the Buchwald group (J. Am. Chem. Soc. 2000, 122, 1360-1370. DOI: 10.1021/ja993912d) has developed highly active and selective catalysts for the α-arylation of ketones. These consist of electron-rich phosphine ligands containing a biphenyl skeleton that are combined with the palladium complex to furnish the active arylation system. Good selectivity was observed in ketones with two enolizable positions (Scheme 6); for example, the arylation of 2-methyl-3-pentanone occurred exclusively at the methylene carbon.

Scheme 6 - Selective arylation of ketones with two enolizable positions.

Arylation reactions carried in the absence of ligand were only successful in a limited number of ketones. Significant effort was devoted to finding a catalytic system applicable to a wide variety of substrates (Table 2).

The results in Table 2 demonstrate the success of this coupling process. With this method, a number of different aryl halides (with several functional groups) can be coupled with a large variety of ketones (aliphatic, aromatic, cyclic and acyclic). An exception is cyclopentanone, which was diverted to an aldol condensation pathway prior to undergoing the coupling reaction.

For the coupling of aliphatic ketones with aryl halides that possess an electron-withdrawing group, a catalyst based on Xantphos was used in combination with NaHMDS or NaOtBu. To enlarge the scope of this process to include base-sensitive groups, the milder base K3PO4 was used. In the event, aryl bromides did react with ketones when K3PO4 was used as the base in the presence of Xantphos / Pd2(dba)3 or 10 as the catalyst. For the arylation of 1,3-diketone, Pd(OAc)2 / 12 / K3PO4 (2.3 equiv) was shown to be the most successful combination.

III. Palladium-catalyzed alpha-Arylation of Amides and Imides

III.1 Amides

The palladium-catalyzed intramolecular α-arylation of amides in the synthesis of oxindoles was reported by the Hartwig group (J. Org. Chem. 1998, 63, 6546-6553. DOI: 10.1021/jo980611y) . Later, because of the high temperatures and amount of catalyst required by this method, the same group improved the process (J. Org. Chem. 2001, 66, 3402-3415. DOI: 10.1021/jo005761z) , focusing on rate acceleration by using sterically hindered N-heterocyclic carbene ligands and alkylphosphines (Scheme 7).

Scheme 7 - Synthesis of oxindoles via intramolecular palladium-catalyzed α-arylation of amides.

The most general ligand was PCy3 , which permitted reactions to be carried at 50 ºC (yields 82-99%); in contrast, PBu3 combined with Pd(0) gave only 21% yield. In most cases, the choice of the ligand was made according to the substrate used. The use of sterically hindered alkyl bis-phosphines required higher reaction temperatures (100 ºC). The best yields were obtained in the formation of α,α'-disubstituted oxindoles 16, 17 with PCy3 (99%). It was demonstrated that a less hindered alkylphosphine gives a faster rate than a more hindered phosphine. The Hartwig group applied this method to the synthesis of asymmetric oxindoles, and tested a variety of optically active phosphine ligands.

Recently, Cossy and co-workers (Org. Lett. 2003, 5, 3037-3039. DOI: 10.1021/ol0350036) reported a general method for the α-arylation of piperidinone enolates (Scheme 8). The best result was obtained with ZnCl2 (48%), the presence of which was found to be crucial. The same result was obtained with ZnBr2, while no product was formed when no zinc was added. When Pd(dba)2 was used, the yield increased to 92%. Several arenes were tested, and the steric hindrance and substituents of the aromatic moiety were found to be important factors: electron-donating groups in ortho, para positions increased the yield while meta substituents decreased it.

Scheme 8 - Palladium-catalyzed α-arylation of 19.
III.2 Imides

The Hartwig method described in the esters section (J. Am. Chem. Soc. 2004, 126, 5182-5191. DOI: 10.1021/ja031544e) can also be applied to ester derivatives with chiral auxiliaries, to form optically active α-aryl carboxylic acids with excellent diastereoselectivity, up to 98% de (Scheme 9).

Scheme 9 - Reactions of silyloxy enamides with aryl bromides.

The use of the zinc additive Zn(O-t-Bu)2 led to improved diastereoselectivity and faster rates. From the many cases examined, it was shown that higher diastereoselectivity is obtained at lower temperatures. Mechanistic studies were presented and it was concluded that the diastereoisomeric ratios observed were the consequence of kinetic selectivity. The conditions for the coupling of the silyl enolates avoids epimerization of the stereocenters.


Several new methods have recently been developed and improved for the intermolecular α-arylation of carbonyl derivatives. The choice of palladium complex, ligand, additives, solvent and temperature are all extremely important for the success of the coupling, and in many cases should be optimized for the individual substrate.

M. M. B. Marques, Org. Chem. Highlights 2004, November 25.