Intermolecular reactions ketone arylation

Some diversity among the carbonyl components of the reaction has also been examined in the intermolecular reactions. For example, two groups have reported that the reaction of Cr(CO)3-complexed aryl aldehydes and ketones with oi,f -unsaturated esters leads to diastereomerically pure lactones, with radical coupling directed anti to the metal tricarbonyl center (Eq. 52) [60]. 

With respect to the substrate scope, ketones are the most efficient nucleophiles although the intermolecular reaction works also well for esters, amides and Weinreb amides (Fig. 2.7). Regarding the Michael acceptor, enones are the best electrophiles with a wide range of substituents tolerated (alkyl, aryl and heteroaryl ketones). a,p-Unsaturated esters, in the case of the intermolecular cyclopropanation, and a,p-unsaturated diimides for the intramolecular reaction, extends the substrate scope of the process (Fig. 2.7). A transition state model for the intramolecular cyclopropanation reaction has been proposed as depicted in Scheme 2.38 for catalyst 65 [106d]. In this model the ammonium salt adopts a conformation that gives the Z-enolate of the nucleophile on deprotonation with the base. The intramolecular conjugate addition of the enolate then takes place through a boat-type transition state. 

Under conditions of high dilution to prevent intermolecular reactions, two allylic halide groups in the same molecule can be coupled to give a cyclic product. Macrocyclic lactones have been made in this way. Coupling occurs only at the primary centres. Note that the nickel reagents do not attack ester groups. Neither do they react with acid chlorides, ethers, nitriles, olefins or alkyl, aryl or vinyl chlorides (in contrast to bromides or iodides). Aldehydes and cyclic ketones are attacked, however, above 40°C affording homoallylic alcohols. 

As described in Sect. 2.1.2, the a-functi(Mialization (tosylation, triflation) of ketones with hypervalent iodine, followed by nucleophilic attack by diverse nucleophiles in an intramolecular fashion offers a convenient entry to various heterocycles [6]. Such a transformation can also be realized in an intermolecular fashion. Along these lines, Togo and coworkers [97] reported an elegant one-pot synthesis of 2,4,5-trisubstituted oxazoles 142 from alkyl aryl ketones 140 and nitriles 141 via an iodoarene-catalyzed oxidation reaction (Scheme 35). In this reaction sequence, reactive aryliodonium species were generated in situ by the reaction of aryl iodide with mCPBA and trifluoromethanesulfonic acid (TfOH). Afterwards, aryliodOTiium species reacted with alkyl aryl ketone to form a fi-keto aryliodonium species. 

Scheme 8.2 Transition-metal-catalyzed intermolecular and intramolecular arylation reactions of ketone...

Arylative or silylative cyclizations of allenyl aldehydes or ketones have been reported (Equations (101) and (102)).459,459a The intermolecular process, that is, three-component coupling reaction of aldehydes, allenes, and arylboronic acids, is catalyzed by palladium as well (Equation (103)).46O 46Oa These reactions are proposed to proceed through nucleophilic attack of the allylpalladium intermediates to the carbonyl groups. 

In intermolecular cyclopropanations [100], it was found better to use a-bromoesters and amides as ylide precursors and a,/ -unsaturated ketones and esters as electron-deficient alkenes - rather than using a-haloketones as the ylide precursor. (For experimental details see Chapter 14.11.4). The reaction gives access to a range of 1,2-dicarbonyl-substituted cyclopropanes (see Fig. 10.5). The al-kene could have an aryl-, alkyl- or indole-substituted ketone, and a-substitution was also tolerated. Notably, Weinreb amides could be used as the ylide precursor and the product subsequently transformed into a diketocyclopropane. Both enan-... 

Sml2 can effectively promote the intermolecular reductive dimerisation of aldehydes or ketones giving rise to symmetrical diols.7 9 Generally, arylalde-hydes and aryl ketones couple within seconds in THF at room temperature. Aliphatic aldehydes and ketones react considerably more slowly several hours are required for the aldehydes, whereas for ketones reaction times of 24 h are usually needed. Nevertheless, these slower couplings can be greatly accelerated by the addition of additives such as HMPA.10... 

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. 

The dimerization of aromatic aldehydes is used for the synthesis of substituted stilbenes. The intermolecular unsymmetrical McMurry reaction is not very important in organic syntheses because of the formation of a mixture of products. However, the reaction of two aryl ketones 4.80 and 4.81 functionalized by a sulfonyl and a hydroxyl group, respectively,... 

Certain tetralones which result from aryl aroylcyclopropanes by tin tetrachloride actionwere utilized in a synthesis of picropodophyllone Similarly, indanones are available from cyclopropyl phenyl ketone whereas reaction of ethyl cyclopropanecar-boxylate in benzene or toluene under Friedel-Crafts conditions gives the same class of compounds in an intermolecular fashion ... 

One of the major problems encountered in this synthesis is the difficulty of obtaining the starting materials (either the a-aminocarbonyl compounds or their acylated derivatives). The former may be prepared by Neber rearrangement of ketoxime tosylates with a base such as ethoxide or pyridine.46 a-Acylamino carbonyl compounds can be prepared directly by the reductive acetylation of oximino ketones.28 38 Balaban and his collaborators47-60 have developed an excellent method for the synthesis of a-acylamino ketones (5). They are obtained in yields of 50-90% by the reaction of azlactones (2-aryl-5-oxazolone, 4) with aromatic hydrocarbons in the presence of aluminum chloride under Friedel-Crafts conditions the reaction may proceed either intermolecularly or intramolecularly. 

The direct intermolecular a-arylation of relatively less acidic ketones with aryl halides, which proceeds by mechanism B, was reported concurrently in 1997 by the groups of Miura, Buchwald, and Hartwig [35-37]. The intramolecular version was also described by Muratake and coworkers in the same year [38,39], while some intermolecular vinylation reaction had been reported [40, 41]. Taking advantage of this, the reaction of carbonyl compounds and related substrates has been studied extensively. Now a variety of ketones are known to be arylated by using appropriate ligands and bases [42-46]. The reaction usually takes place at a less hindered a position (Eqs. 5-7) [19,20]. 

More recently, the use of potassium phosphate has also been reported for the a-arylation of ketones with chloroarenes. KHMDS was the most effective base for the intermolecular arylation of A Af-dialkylamides (eq 35). Higher yields were observed with KHMDS compared to LiTMP. Use of NaOr-Bu resulted in low conversion together with a high level of undesired side products, while LDA appeared to deactivate the system. Coupling of unfunctionalized and electron-rich aryl bromides with A,A-dimethylacetainide afforded a-aryl amides in moderate to good yields when the reaction was conducted with at least 2 equiv of KHMDS base. Diarylation of acetamides as well as hydro-dehalogenation of the aryl halides were side reactions that limited this process. 

C.i.a. Four-Centered Processes. The carbopalladation of a C,C multiple bond with a carbon-palladium single bonds is the key step in the catalytic cycle of the standard Heck reaction, the intermolecular version of which has been used extensively since its discovery for the functionalization and derivatization of aryl and alkenyl halides, as well as alkenyl triflates or the more reactive nonafiates, which are readily available from the corresponding ketones (Scheme 2) (Sect. IV.2.1.2). 

In contrast to the diverse insertion chemistry of vinylpalladium intermediates discussed in Sects. IV.3 and IV.5, the reactions of vinylpalladium complexes with electrophiles had not been reported until recently. Although a single report on the annulation of the o-mer-curio benzaldehyde with diphenylacetylene into the corresponding indenols and inde-nones catalytic in palladium and stoichiometric in copper had been communicated in 1992, the more synthetically useful protocol for the catalytic version of this type of transformation remained unknown until 1999. In this section the intermolecular carbopalladation of alkynes with aryl halides followed by the intramolecular trapping of the formed vinylpalladium species with ketones, aldehydes, and nitriles will be discussed. 

Recently, ruthenium porphyrins have been used as catalysts for tandem carbonyl yhde formation/cycloaddition transformation [200,201]. The dia-stereoselectivity of the reaction with a variety of alkyl- and aryl-substituted a-diazo ketones was found to be highly substrate-dependant. Finally, highly selective intra- and intermolecular couphng reactions of diazocompounds to form cis-alkenes, including organic macrocychc compounds were developed by Che et al. [202]. 

Whereas the intermolecular processes using ketones as source of nucleophile and aldehydes as electrophiles have been extensively stndied, other reactions, nsing either ketones or aldehydes as electrophiles, have been less studied, with reactions implying the use of aldehydes as source of nucleophile and ketones as electrophiles having scarcely investigated. Also the nse of poor reactive ketones such as a,p-unsaturated ketones or even alkyl aryl ketones is still elnsive. 

A variety of catalysts have been used for these hydroary lation reactions of the C-H bonds in aromatic ketones, imines, and 2-arylpyridines. The intermolecular additions of aromatic C-H bonds of aryl ketones to olefins reported by Murai were conducted with RuH fCO) (PPh3)3 as catalyst. [RuH2(H2)(PCy3)2] was shown subsequently to catalyze this process at room temperature and even the much different Rh(I) complex [Cp Rh(C,H3SiMe,),] catalyzes this reaction. Additions of the C-H bonds to N-Bu and N-Bn benzaldimines... 

Oxcarbazepine (Trileptal) has become the most widely prescribed drug for the treatment of epilepsy, both in adults and children. Additionally, oxcarbazepine is also effective in the treatment of mood disorders and mania. In 2005, a five-step procedure was developed for its synthesis. 2 -Aminoacetophenone and 1,2-dibromobenzene were used as starting materials. The key steps accomplished sequentially are palladium-catalyzed intermolecular a-arylation of ketone enolates and intramolecular N-aiylation reactions (Scheme 4.1). 

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