Ketone arylation conditions

Isomerism of Ketoximes.—In the case of aromatic aldehydes they all yield these stereo-isomeric oximes. With the aromatic ketones the condition is different and some yield stereo-isomers and some do not. With symmetrical aromatic ketones in which the two radicals are alike such as di-phenyl ketone, CgHb—CO—C6H,5 no different space relation of the hydroxyl group is possible as the two forms will be identical. When, however, the ketone is unsymmetrical, i.e.j the two radicals are unlike, as in mixed aromatic-aliphatic ketones such as phenyl methyl ketone, CeHs—CO—CH3, or in unsymmetrical di-aryl ketones such as phenyl tolyl ketone, CeHs—CO—C6H4—CHz then the two stereo forms are possible though both forms are not known in all cases. 

The described procedures are easy to carry out even at multi-gram scale and do not require complicated handling. The scope of the reactions are also quite broad since a wide range of aryl halides with different functional groups can be efficiently coupled. Furthermore, the Heck arylation conditions are mild, using only a weak base (potassium carbonate) and moderate reaction temperatures. Alternative methods for the preparation of triarylated ketones and diarylated aldehydes,[8] are mainly those which relies on direct palladium-catalysed coupling of carbon nucleophiles (enolates) with aryl halides in the presence of a strong base.[9-12]... 

This method has two limitations. Yields of ketones are low unless R is a primary alkyl, aryl, or allyl group. The rhodium reagent is expensive, even if prepared rather than purchased. However, it is attractive for synthesis of sensitive ketones, since conditions are mdd. It was used, for example, for synthesis of (S)-(+)-4-methyl-3-heptanone, the alarm pheromone of a fungus-growing ant of the genus A ffa, with complete retention of stereochemistry (equation I). 

Asa contrast, the Mizoroki-Heck reaction in molten salts using ligandless reaction conditions produced the isomerized -arylated ketones. Aryl iodides were first studied, but it was soon shown that aryl bromides were reactive at higher reaction temperatures as well. Lower amounts of catalyst resulted in longer reaction times. The example in Figure 3.30 illustrates a single-step synthesis of the nonsteroidal anti-inflammatory drug Nabumethone [90]. 

Secondary benzylic alcohols are often oxidized to the corresponding ketones under the palladium-catalyzed arylation conditions. In contrast, a unique rhodium-catalyzed arylation of diarylmethanols having a 2-(2-pyridiyl) moiety... 

The acidity of protons in a position of carbonyl compounds can be exploited in Pd-catalysed ketone arylation. This transformation is atom-economical, and is usually performed under mild conditions although strong bases are often employed. 

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. ... 

Tetraphenylethylene Glycol. This prcp iration illustnites the mild conditions under which aryl ketones may undergo bimolecular reduction to com-... 

The carbonylation of aryl iodides in the presence of alkyl iodides and Zn Cu couple affords aryl alkyl ketones via the formation of alkylzinc species from alkyl iodides followed by transmetallation and reductive elimination[380]. The Pd-catalyzed carbonylation of the diaryliodonium salts 516 under mild conditions in the presence of Zn affords ketones 517 via phenylzinc. The a-diketone 518 is formed as a byproduct[381],... 

When aiomatics aie present, they can capture the intermediate vinyl cation to give P-aryl-a,P-unsatutated ketones (182). Thus acylation of alkyl or aryl acetylenes with acyhum salts in the presence of aromatics gives a,P-unsaturated ketones with a trisubstituted double bond. The mild reaction conditions employed do not cause direct acylation of aromatics. 

The wide variety of ketomethylene and amino ketone monomers that could be synthesized, and the abiUty of the quinoline-forming reaction to generate high molar mass polymers under relatively mild conditions, allow the synthesis of a series of polyquinolines with a wide stmctural variety. Thus polyquinolines with a range of chain stiffness from a semirigid chain to rod-like macromolecules have been synthesized. Polyquinolines are most often prepared by solution polymerization of bis(i9-amino aryl ketone) and bis (ketomethylene) monomers, where R = H or C H, in y -cresol with di-y -cresyl phosphate at 135—140°C for a period of 24—48 h (92). 

Cyclic aryl ether ketones have been prepared from l,2-bis(4- uoroben2oyl)ben2ene and bisphenols under pseudo high dilution conditions. These materials undergo ring-opening polymeri2ation in the presence of an anionic catalyst (87). 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

Thakar and Subba Rao showed that reductions with diborane give the same result regardless of whether diborane is generated externally or produced internally by the action of NaBH4 and boron trifluoride or aluminum chloride. They found that alicyclic or dialkyl ketones are not reduced beyond the alcohol stage even under drastic conditions however, diaryl ketones are hydrogenolyzed under normal conditions, while aryl ketones or a,i5-unsatu-rated ketones are hydrogenolyzed, in part, under drastic conditions. 

The photocyclization of N-aryl enamines derived from cyclic or acyclic ketones proceeds under mild conditions to produce 2,3-dihydroindole derivatives (178b). The stereochemistry of the products is predominantly trans, which follows from a photochemical electrocyclic process which should take place in a conrotatory manner (178c,I78d). However, the presence of some cis products is not as easily explained. 

The synthesis is often carried out by subjecting an equimolar mixture of the aryl hydrazine and aldehyde or ketone directly to the indolization conditions without isolation... 

Substituents R, R at the starting oxime 1 can be H, alkyl, or aryl. The reaction conditions for the Beckmann rearrangement often are quite drastic (e.g. concentrated sulfuric acid at 120 °C), which generally limits the scope to less sensitive substrates. The required oxime can be easily prepared from the respective aldehyde or ketone and hydroxylamine. 

Depending on the specific reaction conditions, complex 4 as well as acylium ion 5 have been identified as intermediates with a sterically demanding substituent R, and in polar solvents the acylium ion species 5 is formed preferentially. The electrophilic agent 5 reacts with the aromatic substrate, e.g. benzene 1, to give an intermediate cr-complex—the cyclohexadienyl cation 6. By loss of a proton from intermediate 6 the aromatic system is restored, and an arylketone is formed that is coordinated with the carbonyl oxygen to the Lewis acid. Since a Lewis-acid molecule that is coordinated to a product molecule is no longer available to catalyze the acylation reaction, the catalyst has to be employed in equimolar quantity. The product-Lewis acid complex 7 has to be cleaved by a hydrolytic workup in order to isolate the pure aryl ketone 3. 

There are actually three reactions called by the name Schmidt reaction, involving the addition of hydrazoic acid to carboxylic acids, aldehydes and ketones, and alcohols and alkenes. The most common is the reaction with carboxylic acids, illustrated above.Sulfuric acid is the most common catalyst, but Lewis acids have also been used. Good results are obtained for aliphatic R, especially for long chains. When R is aryl, the yields are variable, being best for sterically hindered compounds like mesi-toic acid. This method has the advantage over 18-13 and 18-14 that it is just one laboratory step from the acid to the amine, but conditions are more drastic. Under the acid conditions employed, the isocyanate is virtually never isolated. 

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