Ketone arylation versions

Another version of the Friedel-Crafts reaction uses acyl halides instead of alkyl halides and yields aryl ketones... 

The a-arylation of carbonyl compounds (sometimes in enantioselective version) such as ketones,107-115 amides,114 115 lactones,116 azlactones,117 malonates,118 piperidinones,119,120 cyanoesters,121,122 nitriles,125,124 sul-fones, trimethylsilyl enolates, nitroalkanes, esters, amino acids, or acids has been reported using palladium catalysis. The asymmetric vinylation of ketone enolates has been developed with palladium complexes bearing electron-rich chiral monodentate ligands.155... 

In 1997, Miyaura and co-workers reported the nonasymmetric version of 1,4-addition of aryl- and alkenylboronic acids to a,/ -unsaturated ketones using rhodium-phosphine complex as the catalyst.97 Later, Hayashi and Miyaura realized the asymmetric 1,4-addition with high catalytic activity and enantioselectivity.98 In the presence of ( y)-BINAP, the reaction of 2-cyclohexenone with 2.5 equiv. of phenylboronic acid gave (A)-3-phenylcyclohexanone with 97% ee (BINAP = 2,2 -bis (diphenylphosphino)-l,l -binaphthyl Scheme 29).99... 

The synthetic utility of many of the substitution reactions described so far is limited because there are well-established thermal routes to the same products. However, a third group of photochemical nucleophilic substitutions involves aryl halides and nucleophiles based on sulfur, phosphorus or, of particular importance, carbon. Two examples are the reaction of bromobenzene with the anion of t-butyl methyl ketone 13.12), and the replacement of bromine by cyanomethyl in 2-bromopyridine (3.13). This type of reaction offers a clear advantage over lengthy thermal alternatives, and intramolecular versions have been used in the synthesis of indoles (e.g. 3.14) or benzofurans from o-iodoaniline or o-iodoanisole respectively. 

Methyla-arylacetates. These esters have been obtained by oxidative rearrangement of alkyl aryl ketones with thallium(III) nitrate in acidic methanol or trimethyl orthoformate (4,496 5, 656 7, 362). A new method, which avoids the toxic TTN, is based on the Woodward version of the Prevost reaction. Thus, treatment of the ketone with iodine (or bromine) and silver nitrate (2 equiv.) in refluxing methanol containing trimethyl orthoformate results in methyl a-arylacetates in 90% yield from simple substrates. Yields are lowered by electron-withdrawing substituents on the aromatic group and by a-branching in the alkyl group.2... 

Since 1,4 addition of a variety of appropriate aryl caibanions to 36 failed, an intramolecular version of the Heck reaction was examined. With this end in view, the ketone 36 was reduced stereospecifically to the corresponding allyl alcohol which was then protected as its p-methoxybenzyl ether 37. The amine, obtained on reduction of the azide 37, was condensed with 6-bromopiperonylic acid to furnish the amide 38. 

These chiral acyl donors can be used for quite effective kinetic resolution of racemic secondary alcohols. For example, enantiomeric aryl alkyl ketones are es-terified by the acyl pyridinium ion 8 with selectivity factors in the range 12-53 [10], In combination with its pseudo-enantiomer 9, parallel kinetic resolution was performed [11], Under these conditions, methyl l-(l-naphthyl)ethanol was resolved with an effective selectivity factor > 125 [12]. Unfortunately, the acyl donors 8 and 9 must be preformed, and no simple catalytic version was reported. Furthermore, over-stoichiometric quantities of either MgBr2 or ZnCI2 are required to promote acyl transfer. In 2001, Vedejs and Rozners reported a catalytic parallel kinetic resolution of secondary alcohols (Scheme 12.3) [13]. 

After exchange of the protecting group, the Weinreb amide 111 (an alternative to nitriles for the formation of ketones discussed in detail in Strategy and Control) reacted with the aryl Grignard reagent to give, after reduction, 112—the protected version of the alcohol 106 required for cyclisation. 

Aryl and vinyl sulfonate esters are reactive toward oxidative addition, and the perfluoroaUcyl versions are useful substrates in the Heck reaction. Conditions can be mild, comparable to those for vinyl iodide reactions. The enol (vinyl) triflates are particularly attractive, since they are prepared directly from the corresponding ketone (equation 21). ... 

Fused pyrazole compounds have been prepared from A -alkyl-substituted pyrazoles. For example, a palladium-catalyzed/norbornene-mediated sequential coupling reaction involving an aromatic sp C-H functionalization as the key step has been described, in which an alkyl-aryl bond and an aryl-heteroaryl bond are formed in one pot. A variety of highly substituted six-membered annulated pyrazoles 433 were synthesized in a one-step process in moderate yields from iV-bromoalkyl pyrazoles 431 and aryl iodides 432 (Equation 87) <20060L2043>. An intramolecular cyclization version has also been reported. Exposure of 2equiv of -butyllithium to l//-pyrazole-l-alkanoic acids 434 afforded the cyclic ketones 435 via a Parham-type cyclization process (Equation 88) <1997SL1013>. 

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... 

The Fries rearrangement used for the preparation of aryl ketones from phenolic esters is now one of the most significant reactions in the synthetic chemistry of aromatic compounds, both in the classical version (equation 99) and in the newest modifications (see Section IV.D.3). 

In an attempt to improve the ability to recycle the catalyst, fluorous versions of the oxazaborolidine have been constructed.12 Pre-catalyst 29 could be prepared in five steps. This species was able to form the requisite chiral catalyst 30 in situ. Ketones 31 could be reduced to alcohols 32 in good to excellent chemical and optical yields. It was noted that aryl... 

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]. 

Several versions of palladium-catalyzed coupling reactions have been used to convert o-nitroaryl halides to o-nitrophenylacetaldehydes or o-nitrobenzyl ketones. Coupling with trimethylsilylethyne gives aryl alkynes which can be converted to o-nitrophenylacetaldehyde enol ethers by sodium ethoxide (Scheme 21) <86CPB2362>. 

When allylic alcohols are used as an alkene component in HR, elimination occurs from an oxygen-bearing carbon, and aldehydes or ketones are obtained, rather than jS-arylated allylic alcohols [68,69]. The reaction of methallyl alcohol (113) with a halobenzene is a good synthetic method for dihydro-2-methylcinnamaldehyde, an important fragrant compound 114. The allylic alcohol 115 is not formed. An intramolecular version of the aldehyde formation was applied to the preparation of the key intermediate 117 from 116 in the total synthesis of saponaceolide [70]. 

This area of research most probably began when Semmelhack and co-workers reported both inter- and intramolecular versions of Ni-catalyzed arylation of lithium enolates derived from ketones shown in Scheme 7,[i5],[i6] jjjjg vork, however, was not developed further perhaps due, at least in part, to the fact that the same organic transformation was achieved much more satisfactorily by resorting to the SrnI reaction. ... 

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. 

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