Arylation of ketones

Despite the great success of the transmetalation process in the enantiose-lective arylation of ketones, its extension to allylation or alkynylation reactions failed, providing the corresponding tertiary alcohols with enantiomeric excesses never higher than 50% ee. On the other hand, more success has been found in the alkenylation of ketones. The process started with the hydrozirconation of terminal alkynes to give the corresponding alkenylzirconium intermediates, which were transmetalated by reaction, in this case, with various ketones in the presence of the HOCSAC ligand. This protocol tolerated the presence of other carbon-carbon multiple bonds on the alkyne, as well as different functionalities and achieved excellent results for alkyl ketones, a,(3-unsaturated ketones and even dialkylketones, as shown in Scheme 4.22. 

Scheme 4.19 Arylations of ketones with boronic acids and HOCSAC ligand.

Scheme 4.25 Alkylation and arylation of ketones with trans-l -arenesulfonylamino-2-isoborneolsulfonylaminocyclohexane ligands.

In 2008, these authors reported a new strategy to attach chiral trans-l-arenesulfonylamino-2-isoborneolsulfonylaminocyclohexane to an achiral Frechet dendron (polyether having a repeated 3,5-dioxybenzyl structure) by a radical approach.The dendrimers obtained were successfully used in the enantioselective nucleophilic alkylation and arylation of ketones, providing... 

Scheme 4.26 Polymer-supported traw5-l-arenesulfonylamino-2-isoborneolsulfony-laminocyclohexane ligand for alkylation and arylations of ketones.

Scheme 4.27 Frechet dendrimeric trawi-l-arenesulfonylamino-2-isoborneolsulfonyl-aminocyclohexane ligand for alkylations and arylations of ketones.

Scheme 11.12 provides some examples of the preparative use of the SRN 1 reaction. Entries 1 and 2 involve arylations of ketone enolates, whereas Entry 3 involves a dianion. Entry 4 is an example of a convenient preparation of arylphosphonates. Entry 5 is an example of application of the SRW1 reaction to a chloropyridine. 

A very common combination in Pd-catalyzed domino reactions is the insertion of CO as the last step (this was discussed previously). However, there is also the possibility that CO is inserted as the first step after oxidative addition. This process, as well as the amidocarbonylation, the animation, the arylation of ketones, the isomerization of epoxides, and the reaction with isonitriles will be discussed in this section. 

Buchwald and co-workers have developed highly active catalysts consisting of bulky, electron-rich phosphine ligands with a biphenyl backbone combined with Pd(OAc)2 for the arylation of ketones or nitroalkanes (Eq. 5.72).115... 

Enantioselective arylation of ketones can be realized either with the standard BINAP ligand, which requires harsh conditions and a high loading of catalyst to produce high yields (53),202 or with newer, MOP-type ligands (L4) (Section 9.6.3.4.2) under mild conditions and only one-tenth as much catalyst., 204... 

The asymmetric arylation of ketone enolates represents an attractive method for the preparation of optically active carbonyl compounds with a stereogenic quaternary center at the a-position to the carbonyl group. Such types of compounds are important intermediates for natural product synthesis. Replacement of BINAP by 109 provides... 

The push-spectator stabilization system enables one to employ various alkyl groups with different types of steric environment, which differentiate amino(alkyl) carbenes dramatically from the NHCs as ligands. Taking advantage of their steric and electronic properties, Bertrand et al. nicely demonstrated the utility of CAACs as ligands in the palladium catalyzed a-arylation of ketones. Depending on the nature of the aryl chloride used, dramatic differences were observed in the catalytic activity of Pd-complexes with CAACs featuring different types of steric environment [36]. 

Scheme 12 a-Arylation of ketones catalyzed by CAAC-Pd complexes... 

Palladium-catalyzed a-arylation of ketones is performed with arylene dihalides and bifunctional aromatic ketones 148 to result in the bond formation at the r/) -a-carbon of the ketone, leading to polyketone 149. The reaction is carried out in the presence of Pd(0) and various phosphines. Several bidentate phosphines and bulky alkylphosphines such as dppf, BINAP, PCys, and P Bu3 are shown to be effective, while PPh3 results in no reaction. Arylene dibromide and diiodide are applicable as the co-monomers. The polymerization reaction is carried out in THE in the presence of NaO Bu at 75 °C under N2, and polymers 149 are isolated in 60-80% yields (M = 7000-15 000). Polyketone 149 is further transformed to conjugated polymer PPV by reduction of the ketone moiety with LiAlH4 followed by dehydration with an acid (Equation (69)). 

The regiochemistry of arylation of ketones has not been studied systematically, but there are sufficient data in the literature to allow reasonable predictions to be made. With enolates having one r-alkyl group attached to the carbonyl (e.g. "Cl COBu ) or with those derived from aryl alkyl ketones, clearly no prob-... 

Buchwald has designed a hindered dialkylphosphino-binaphthyl ligand (3) that is much more active than the original ligand for asymmetric arylation of ketone enolates. Reactions occur at room temperature using only 2 mol % catalyst with enantioselectivities up to 94% [41]. Additionally, the Buchwald group has developed an electron-rich monodentate ligand (4) capable of vinylation of ketone enolates with up to 92% ee [42]. 

Tellitu, I. Dominguez, E. Towards a facile synthesis of triarylethanones Pd-catalyzed arylation of ketone enolates under homogenous and heterogeneous conditions. Tetrahedron 2004, 60, 2393-2408. 

An easy and simple synthesis of different chiral fran -l-arenesulfonylamino-2-isoborneolsulfonylaminocyclohexane derivatives (41) has been reported.108 These ligands have proved to be excellent promoters for the catalytic enantioselective alkylation and arylation of ketones (up to 99% ee), very good for the alkenylation process, and modest for the allylation and alkynylation reactions. 

Fraboni, A., Fagnoni, M. and Albini, A. (2003) A novel a-arylation of ketones, aldehydes, and esters via a photoinduced SN1 reaction through 4-aminophenyl cations. Journal of Organic Chemistry, 68, 4886-4893. 

A versatile strategy for efficient intramolecular oc-arylation of ketones was achieved by the reaction of silyle enol ethers with PET-generated arene radical cations. This strategy involved one-electron transfer from the excited methoxy-substituted arenes to ground-state DCN [42]. Pandey et al. reported the construction of five- to eight-membered benzannulated as well as benzospiroannulated compounds using this approach (Sch. 20) [42a]. The course of the reaction can be controlled via the silyl enol ether obtained... 

The cross-coupling of aryl halides and enolates is a powerful method to prepare a-arylated carbonyl compounds that are difficult to access through classic organic chemistry [29]. (NHC)Pd(allyl)Cl species [30] were the first NHC-bearing complexes used as pre-catalysts for the a-arylation of ketones [31,32]. More recently, novel (IPr)Pd(acac)Cl complexes have shown remarkable catalytic activity in this transformation [33]. From aryl chlorides, excellent yields were obtained after short reaction times at 60 °C, the lowest temperature reported to date with a carbene-based system (Table 1). 

Several papers describing the direct intermolecular a-arylation of ketones proceed by mechanism D were published in 1997 [46-48]. Only a single example had been disclosed in a patent by the year [49]. The authors found that aryl iodides react with benzyl ketones in the presence of PdCl2 using CS2CO3 as base (Eq. 8) [46,50]. Bromobenzenes can also be used for this reaction when a phosphine ligand is added. 

Muratake et al. reported the intramolecular a-arylation of ketones [55,56]. Thus, polycyclic compounds are readily obtained from aromatic keto-bromides and keto-triflates (Eq. 16). Bromo-amides can give the corresponding cycliza-tion products (Eq. 17) [52]. Related intramolecular vinylation reactions to give aliphatic polycyclic compounds have also been reported (Eq. 18) [57,581. The intramolecular cyclization of aromatic halo-ketones under carbon monoxide, which proceeds by mechanism C, gives the corresponding a-acylated products (Eq.l9) [321. 

The reaction is considered to involve two mechanistic patterns i.e.,the reactions of arylpalladium intermediates with (a) phenolates at the ortho-positions, this being similar to the a-arylation of ketones (see Sect. 2.2 and Scheme 4), and with (b) thus formed biphenyl-2-ols as in Eq. (56). While the latter proceeds in both DME and xylene, the use of the less polar solvent is essential for the former to occur effectively. However, the intramolecular cyclization of halophenyl-linked phenols is known to occur in DMA [ 122]. It is worth noting that 0-arylation of phenols to give diaryl ethers occurs when bulky phosphine ligands are used (Eq. 60) [26-28]. This may imply that in the aryl(aryloxy)palladium intermediates, reductive elimination to give the ethers is enhanced by the ligands (Scheme 4). 

The a-arylation of ketones, such as cyclohexanone, can be achieved using different methods. A convenient route by Pinhey et al.89), reacts cyclohexanone-2-carboxylic esters with aryllead triacetates in pyridine. The protection of the P-carboxylic ester prevents a,a-di- or even higher arylations in a -positions. The ester group can be removed by basic hydrolysis and mild thermal decarboxylation or by heating in wet dimethylsulfoxide with sodium chloride (120-180 °C)90). Barton et al. 91) have found a similar a-arylation route using the less electrophilic triphenylbismuth carbonate. In both cases probably the lead- or bismuth-enolates, respectively, are the first inter-... 

Its Pd- and Ni-complexes have also been used successfully in C-C coupling reactions (08JA195). For example, the asymmetric a-arylation of ketones catalyzed by the DIFLUORPHOS-Pd complex occurred in high ee and high yield (Scheme 17). In many cases involving electron rich and neutral aryl triflates, the ee s are typically higher than those... 

In the last years several publications appeared describing palladium-catalyzed a-arylations of ketone enolates for the synthesis of a-aryl ketones, involving ketone eno-lates, silyl enol ethers and intramolecular a-aiylation of ketone enolates . In this process, an enolate is generated from a ketone in the presence of an aryl halide, and a palladium catalyst couples this enolate with the aryl halide. Iwama and Rawal proposed... 

Until recently, a-substitution of carbonyl compounds was largely restricted to those cases where alkyl groups, such as Me, allyl, and benzyl, were introduced via classical enolate alkylation. a-Aiylation of ketones with aryl halides can be effected using K in NH3 [120-123]. However, this reaction does not appear to be satisfactory for selective -alkenylation and a-alkynylation. -Arylation of ketones has also been catalyzed by Ni [124] and Pd [125,126]. The Pd-catalyzed version employed enolstannanes. This reaction has also been applied to a-alkenylation [127]. However, these reactions appear to be of very limited scope. Thus, the Pd-catalyzed procedures appear to be satisfactory mainly for a-substitution of methyl ketones. Furthermore, none of them addresses the critical question of how to control the regiochemistry of c-substitution, i.e., a vs. a. Critically needed from the viewpoint of selective synthesis were... 

Benzyl ketones. Pd(0)-catalyzed arylation of ketones is regioselective. Reaction at the less substituted site is observed. 

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