Ketone arylation NHCs

Scheme 8.17 Proposed catalytic cycle for the a-arylation of ketones with (NHC)Pd(OAc)2 system, as described by Nolan and coworkers [43].

Monoligating NHCs proved extremely successful in ketone arylation. The groups of Nolan and Bertrand reported catalysts 68 and 69-71, respectively (Figure 9.15). Whilst complex 68 was based on commercially available IPr and had a rather unremarkable structure, Bertrand s catalysts were the first reported complexes of so-called cyclic alkyl(amino)carbenes, or CAAC. These ligands display unique steric properties and they are also stronger a-donors... 

A limited number of studies focussed on the development of NHC-Pd catalysts for polymerisation reactions. The a-ketone arylation reactions, described in Section 9.2.8, can be applied to the polycondensation of haloarylketones. Thus, Matsubara reported the polymerisation of bromo- or chloro-propiophenone catalysed by mixtures of [Pd(OAc)2] and IPr HCl or IMes HCl (3 mol% [Pd]). The former system was more active and the use of excess imidazolium salts resulted in decreased activity, due to the formation of bis-NHC Pd species. Chung reported the application of Nolan-type Pd-allyl catalysts (see Figure 9.8) to the polymerisation of ester-functionalised norbornene monomers. " These substrates are typically more difficult to polymerize than non-functionalised monomers, and such catalysts efficiently catalysed the polymerisation of simple... 

The abihty to perform oxidations without generating species harmful for potential intermediates of further transformations is important to perform multistep synthesis, such as the domino reactions described below (Section 5). In this respect, the use of aryl hahdes as readily available, stable and cheap oxidants (hydride acceptors) is a powerful option due to the production of inert, dehalogenated aryl by-products in anaerobic conditions. Commercially available Pd and Ni complexes with NHC ligands were found to be active in a temperature-controlled domino oxidation/R-ketone arylation with aryl halide. ... 

Various aryl-alkyl ketones and dialkyl ketones could be reduced using the Rh(III) - NHC catalyst 55 in high yields (82-96%) and with good to excellent enantioselectivities (67-98% ee) (Scheme 34). 

Xia and co-workers synthesised a number of Pd-NHC complexes (33, 34, 36) for carbonylative Suzuki reactions (Fig. 9.6) [41], Various aryl iodides were carbonylatively coupled (P = 1 atm) with either phenylboronic acid or sodium tetraphenylborate. All the complexes were highly active, but 33 provided the best results with >76% selectivity for ketone in all the reactions. Xia followed this work with the double carbonylation of various aryl iodides with several secondary amines using the catalysts [CuX(Mes)] (37-X) and [Cu(IPr)X] (38-X) (X = I, Br, Cl) (3 MPa, 100°C, 10 h) (Scheme 9.7) [42],... 

Homoenolate Reactivity The ability to generate homoenolates from enals and its application to the preparation of y-butyrolactones 30, through reaction with an aldehyde or aryl trifluoromethyl ketone, was reported independently by Glorius [8], and Bode and Burstein [9] (Scheme 12.4). A sterically demanding NHC catalyst is required to promote reactivity at the d terminus and to prevent competitive benzoin dimerisation. Nair and co-workers have reported a similar spiro-y-lactone formation reaction using cyclic 1,2-diones, including cyclohexane-1,2-dione and substituted isatin derivatives [10]. 

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]. 

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). 

Chiral N-arylated imidazolinylidene ligands have been employed in the palladium(II) catalyzed aerobic oxidation of secondary alcohols to the corresponding ketones [55]. The chiral variant of this reaction, which does not generate a new element of chirality, is again based on the kinetic resolution of racemic mixtures. The active catalyst is formed in situ by a combination of two precursors, a dinuclear NHC-palladium(II) complex and an achiral (acetate) or chiral base ((-)-sparteine) (Scheme 18). 

The cross-coupling of aryl halides and enolates is a powerful method to generate new C-C bonds and it has been extensively investigated using various palladium catalysts [70]. Extremely active NHC/Pd systems have been reported for the a-arylation of esters at room temperature [71] and for the arylation of amides [72]. Ketones that possess a-protons can be deprotonated in the presence of strong bases, a-Arylation of ketones can be performed in the presence of a catalytic amount of (NHC)Pd(allyl)Cl as catalyst and NaO Bu as base (Scheme 19). 

Lipshutz and coworkers have developed copper hydride complexes with diphosphine ligands that catalyze the asymmetric hydrosilylation of aryl ketones at low temperatures (-50 to -78 °C) [68]. Nolan and coworkers discovered that copper complexes with NHC ligands are very efficient catalysts for the hydrosilylation of ketones, including hindered ketones such as di-cyclohexyl ketone and di-tert-butyl ketone [69]. 

It is used for making NHCs for metal catalysed a-arylation of acychc ketones, e.g. propiophenones, and amination of haloarenes [Matsubara et al. J Org Chem 72 5069 2007], It has been sirlfonated for making sulfonated anilines, and consequently sulfonated NHCs, which provide water soluble Pd-NHCs used for Suzuki coupling of arylhalides with arylboronic acids in aqueous medium [Fleckenstein et al. Chem Commun 2870 2007],... 

The Inamoto group [44] has reported that the NHC-based pincer complex 30 is an effective catalyst for the cross-coupHng of aryl haUdes and butyl acrylate (Eq. (5.33)). This catalytic system is appHcable to aryl iodides, aryl bromides, and activated aryl chlorides, and compatible with functional groups including nitrile, ketone, and aldehyde. Notably, the reaction of 4-bromobenzonitrile can be retarded by a drop of mercury, suggesting that the catalytic system may be heterogeneous. 

The combination of Ni(COD)2 and l,3-di-ferf-butylimidazol-2-ylidene (ItBu) was demonstrated to effectively catalyse an intramolecular alkene hydroacylation to construct five- and six-membered benzocyclic ketones in good to excellent yields (Scheme 14.71). Al-aryl-substituted NHCs are not effective for this transformation. The reaction is proposed to proceed via a process as shown in Scheme 14.72. Thus, 2-allylbenzaldehyde coordinates to Ni(0)/ItBu to form complex A. The oxidative cyclisation of A gives a nickelacycle intermediate B. B undergoes p-hydride elimination and reductive elimination to produce final product C, along with regeneration of the catalyst. ... 

Nickel-catalyzed ketone and aldehyde hydrosilylations have been developed with well-defined Ni(II) hydrides using phosphine anilide ligands (Scheme 3-84). This process is tolerant of a variety of functional groups including aryl halides. In mechanistically distinct processes, nickel(O) complexes of NHCs were shown to catalyze ketone hydrosilylations using carbohydrate-derived silanes in a process that allows reductive glycosylations of ketones. Chemoselectivity of the latter method was optimal in the presence of Ti(OR)4 additives. 

Orfho-disubstituted aryl iodides as representative examples of sterically hindered substrates are more challenging in palladium-catalyzed coupling reactions. In this respect it is interesting to note that Martin et al. reported a synthesis of sterically hindered aryl ketones by using the NHC palladium complex PEPPSI-iPr [34]. Several diaryl ketones were produced in moderate to good yields by this method (Scheme 4.18). 

In 2010, Biju and Glorius [62] reported the NHC-catalyzed hydroacylation of arynes. A variety of aldehydes reacted with the arynes, generated in situ from 2-trimethylsilylaryl triflate and KF, to give benzophenones, a,p-unsaturated and other aryl ketones (Scheme 7.42). 

A C2-symmetric copper-bound NHC gives excellent ees in fast room-temperature hydrosilylation of dialkyl and aryl alkyl ketones. ... 

There are a limited number of group VHI-X metal-based catalytic systems active and selective in asymmetric hydrosilylation of 0=0 bond. These few systems include Fe(OAc)2/DUPHOS active in hydrosilylation of aryl methyl ketones with (EtO)2MeSiH or PMHS (301,302), ruthenium complexes bearing oxazolinylferrocenephosphine ligand (303), or chiral bis(paracyclophane)-substituted (NHC) ligands in hydrosilylation of aryl alkyl ketones with H2SiPh2 (304) and iridium(I)/DIPOF system active in hydrosilylation of acetophenone with diphenylsilane. 

The palladium-catalyzed a-arylation of ketones has become a useful and general synthetic method [106]. Initial studies required preformed zinc [378] or tin enolates [379]. On the other hand, Ni-mediated [380] or Ni-catalyzed couplings are also known. A great development of the reaction has occurred since 1997 based on the use of new catalysts with electron-rich alkylphosphines and NHCs as ligands [173, 381]. The reactions resemble cross-couphng processes in which the enolates behave as the nucleophilic organometaUic reagents (Scheme 1.47). 

Formation of a CyjP-Pd-L (L = NHC) has been proposed as the catalyticaUy active species in the aryl amination and a-arylation of ketones by Nolan in a system starting from a paUadacyde containing an NHC [383]. 

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