Palladium-catalyzed a-arylation of carbonyl

A. Culkin, J. F. Hartwig, Palladium-Catalyzed a-Arylation of Carbonyl Compounds and Nitriles, Acc. Chem. Res. 2003, 36, 234-245. 

Palladium-catalyzed a-arylation of carbonyl derivatives and its applications in the synthesis of natural products 05CJO282. 

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. 

Palladium-CatalYzed a-Arylation of Carbonyl Compounds and Nitriles I J5... 

Scheme 1.47 Proposed mechanism for the palladium-catalyzed a-arylation of carbonyl compounds.

The exact mechanism of this process, however, remains unclear. It should be noted that the C-H activation in this case involves a C-H bond that is fairly acidic due to the carbonyl group, and the palladium-catalyzed a-arylation of esters by aryl halides is a well known process [68-71], Thus, one might argue that activation of this specific homobenzylic C-H bond may involve formation of a five-membered ring palladacycle, which undergoes P-hydride elimination, rather than palladium migration. 

This suggests that in the case that both intramolecular C- and 0-arylations are of geometrically equal possibility, the former preferentially takes place. The reaction of o-bromobenzaldehydes with dibenzylketones gives l,3-diaryl-2-naphthols that may be useful materials as bulky 0-ligands (Eq. 24) [62]. This cyclization involves palladium-catalyzed a-arylation and base-promoted dehy-drative condensation. Treatment of o-iodoanilines with ketones produces indole derivatives (Eq. 25) [63]. In this case, dehydrative condensation between the amino group and the carbonyl group occurs initially and the subsequent car-bopalladation (mechanism A) leads to the products. 

The Marsden group has published a collection of articles detailing the synthesis of heteroatom containing C3 quatemized oxindoles [64—66]. The transformations involved the palladium-catalyzed intramolecular arylation of anilides bearing either amino or alkoxy functionality alpha to the anilide carbonyl. Under microwave conditions, a variety of 3-alkoxy-3-aryl, 3-amino-3-aiyl, or 3-amino-3-alkyloxin-doles have been prepared in racemic form. In one example, 3-indolyloxindole 1 7 was prepared in 65% yield (Scheme 28). 

Extension to carbocyclization of butadiene telomerization using nitromethane as a trapping reagent is reported (Eq. 5.48).72 Palladium-catalyzed carbo-annulation of 1,3-dienes by aryl halides is also reported (Eq. 5.49).73 The nitro group is removed by radical denitration (see Section 7.2), or the nitroalkyl group is transformed into the carbonyl group via the Nef reaction (see Section 6.1). 

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... 

Heck carbonylation involving the oxidative addition of aryl halides is not applicable to aliphatic halides, since alkyl halides react directly with nucleophiles. Tsuji developed a process of carbonylating allyl carbonates to form carboxylic esters by palladium-catalyzed carbonylation that is applicable to aliphatic substrates [60]. The process probably involves (a) the oxidative addition of allyl carbonates to Pd(0) species to form r/ -allyl palladium species, (b) CO insertion into the allyl-Pd bond to give acylpalladium species, (c) decarboxylation of the carbonate ligand to give alkoxide, and (d) liberation of butenoate esters by combination with the alkoxides as shown in Scheme 1.21. 

With the same reaction as that of alkoxycarbonylation, the first palladium-catalyzed amidation reaction of aryl-X compounds was again developed by Heck and his group. They demonstrated that by carbonylation reactions, secondary and tertiary amides are conveniently produced [118]. More specifically, (hetero)aryl bromides and vinyl iodides were reacted with primary or secondary amines under atmospheric CO pressure at 60-100 °C in the presence of 1.5 mol% PdX2(PPh3>2. Stoichiometric amounts of a tertiary amine were required to neutralize the formed acid if weakly basic amines were used as nucleophiles. 

More recently, an improved protocol for palladium-catalyzed alkoxycarbony-lation of aryl chlorides with alkyl formates was developed by Beller and colleagues [225]. In the presence of palladium(II) acetate/n-butylbis(l-adamantyl)phosphine, and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base, for the first time non-activated chloroarenes could be conveniently carbonylated in good yields (Scheme 2.28). In this report, it has been shown that the catalyst system presented does not need the presence of ruthenium co-catalysts. 

The palladium-catalyzed arylation of carbonyl compounds is proving to be a very important process. Both inter- and intra-molecular variants are known. For example, the synthesis of the pharmaceutically important oxindole framework has been accomplished via the palladium-catalyzed cyclization of a-chloroacetanilides that involves C-C bond formation at an ortiio-position on the aromatic ring (eq 108). ... 

Aryl Halide Carbonylations. Palladium-catalyzed carbony-lation of aryl halides is an efficient way to produce carboxylic acid derivatives. Aminocarbonylation of aryl chlorides has heen performed using Mo(CO)6 as the carbon monoxide source and a catalyst derived from TTBHBF4 andpalladacycle 1 under microwave irradiation (170 °C). Tbe catalyst system was also applied to the carbonylation of 4-chloro-l-trifluoromethylbenzene in hutanol to... 

Transmetallation is also a key step in the palladium-catalyzed Buchwald-Hartwig-Miura arylation of carbonyl compounds [171] with its manifold stereoselective variants [172]. In the general catalytic cycle, illustrated in Scheme 2.53, a ketone enolate 179 [173] reacts with the palladium(II) intermediate 178, resulting from oxidative addition, in a transmetallation step to give palladium enolates that are assumed to exist as an equilibrium between C-bond tautomer 180 and O-bound 181. Their reductive elimination under regeneration of the palladium(O) catalyst and concomitant release of the a-arylated ketone 182 closes the catalytic cycle. 

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