Alkyl aryl ketones, synthesis

Alkyl aryl ketones are convenient intermediates for preparing other substituted aromatic and heteroaromatic compounds. Challenger and co-workers " acetylated thieno[2,3-h]thiophene (1) with acetyl chloride and stannic chloride [Eq. (59)]. The 2-acetylthieno[2,3-A]-thiophene obtained by this method was reduced to the 2-ethyl derivative (20) identical with the product of an independent synthesis. ... 

Asymmetric reduction of a,fi-enon s. This combination of reagents (1 1) in conjunction with N-cthylaniline (2 equivalents) reduces alkyl aryl ketones to alcohols with high stereoselectivity.1 Under these conditions 2,/1-unsaturated ketones arc reduced to optically active (S)-allylic alcohols. Optical yields of 80 98% have been reported for open-chain enones. Reduction of cyclic enones is somewhat less efficient. The method was used to reduce 1 to 2, which has been used as an intermediate in an anthracyclinone synthesis.2... 

A retrosynthetic analysis of a,/J-unsaturated ketones leading to various methods of synthesis is outlined in Section 5.18.2, p. 798. These methods are equally applicable to aromatic aldehydes. Aromatic aldehydes condense with aliphatic or mixed alkyl aryl ketones in the presence of aqueous alkali to form a,[i-unsaturated ketones (the Claisen-Schmidt reaction). 

Moreover, reduction of alkyl aryl ketones can be used to access optically pure secondary aryl alkyl amines, as illustrated in an enantioselective synthesis of SDZ-ENA-713 (ll)60 and as we have demonstrated in a related process (Scheme 16.8). 

The present review covers all the available published data on the Pfitzinger reaction beginning from the time of its discovery. The investigated material has been classified on the basis of the structure of the initial ketones separate sections cover the reactions of isatins with dialkyl ketones, keto acids, alkyl aryl ketones, and alkyl hetaryl ketones and also with cyclic ketones. Papers describing the synthesis of 4-quinolinecarboxylic acids by methods related to the Pfitzinger reaction are discussed in a separated section. 

Finally, the hydroboration-amination method via azides might be the key step in the synthesis of alkyl aryl ketones involving a free radical mechanism as opposed to the usual ionic pathway [64,65] (Scheme 23). 

BORSCHE - BEECH Aromatic Aldehyde Synthesis Synthesis of aromatic aldehydes and of alkyl aryl ketones from aidoxanes or semicaibazones ai aromatic rlazonium salts... 

The rate of acetylation of 0-(hydrox3Tnethyl)cellulose (and other hydroxy compounds) by mixtures of carboxylic acids and their anhydrides has been found to increase greatly in the presence of trifluoroacetic acid. The acceleration is very much less with mono- and tri-chloroacetic acids, presumably because they form unsymmetrical anhydrides which are less effective acylating agents than acyl trifluoroacetates. The exceptional acylating power of the latter anhydrides is shown by their use in the synthesis of alkyl aryl ketones from polyalkylbenzenes, phenyl ethers, furan, and thiophene under mild conditions. The principle has been extended to include acids... 

Among a variety of organometallics for this purpose, organoboron compounds were first used by Kojima for the synthesis of alkyl aryl ketones [167]. The action of Zn(acac)2 in this reaction (Scheme 2-61) is ascribed to the formation of a RCOPd (acac) species which undergoes transmetallation without assistance of bases (Scheme 2-20). 

Asymmetric reduction of or y-functionalized alkyl aryl ketones provides a wide variety of chiral amino alcohols. Commercial -chloropropiophenone is reduced with borane-tetrahydrofuran adduct catalyzed by oxazaborolidine 45 to provide the chlorohydrin in over 99 % yield with 94 % ee. The resulting alcohol is a key intermediate for synthesis of the R form of fluoxetine (Prozac ), a serotonin-uptake inhibitor [53]. Using hydrogenation processes the functionalized amino ketones are converted directly into the respective products [8, 43e],... 

Replacement of the normal pyrethroid ester by alternative linkages usually leads to diminution of biological activity. One important exception to this general phenomena is several oxime ether derivatives, in particular, 3-phenoxybenzyl derivatives of various alkyl aryl ketones. Pyrethroid esters derived from certain 2-substituted-[1,1 -biphenyl]-3-methanols have been shown to possess initial and residual activity surpassing that of esters derived from 3-phenoxybenzyl alcohol. Now it has been demonstrated that the same enhancement of activity was observed for alkyl aryl oxime ethers of certain [1,1 -biphenyl]-3-methanols compared to the corresponding 3-phenoxybenzyl alcohol derived oximes. The synthesis, biological activity, including soil activity, structure-activity relationships and toxicity of several of these biphenylmethyl oxime ethers are described. 

Oxidation of easily enoUzable ketones such as alkyl aryl ketones affords either a-oxylated ketones or carboxyhc acid derivatives via oxythallation of the enol forms, the products depending on the kind of Tl(lll) salts and/or solvents employed (Scheme 9.24). Use of TTN usually induces aryl group migration leading to the formation of carboxyhc acids or their esters [26], making this oxidative transformation useful for organic synthesis (Schemes 9.25 [27], 9.26 [28], 9.27 [29] and 9.28 [30]). Use of TTA, thallium tosylate [ l l(OTs), ], thallium triflate [ l1(()Tf), ], and thallium mesylate [ l1(()Ms)j, on the other hand, produces -oxylated ketones which sometimes further react to give useful compounds (Schemes 9.29 [31], 9.30 [32], 9.31 [33], 9.32 [34] and 9.33 [35]). 

Kawano Y, Togo H (2009) lodoarene-catalyzed one-pot preparation of 2,4,5-trisubstituted oxazoles from alkyl aryl ketones with mCPBA in nitriles. Tetrahedron 65 6251-6256 Jarikote DV, Siddiqui SA, Rajagopal R, Daniel T, Lahoti RJ, Srinivasan KV (2003) Room temperature ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under ambient conditions. Tetrahedron Lett 44 1835-1838... 

Synthesis of alkyl aryl ketones from ar. aldehydes via 1,3-dloxolanes... 

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. 

Baker and Ollis s method—Acylation of an alkyl aryl ketone with ethyl oxalyl chloride in pyridine under mild conditions was first used in a synthesis of 3-arylchromones (isofiavones) [64]. The mechanism of this convenient method is probably as shown in Figure 2.2 [65]. 

When the alkyl aryl ketone contains more than one phenolic group, an additional molar equivalent of acyl chloride should be added and the ester group so formed may be hydrolysed at the end to regenerate the hydroxyl group [65]. This method has been used in the synthesis of the 2-carboxylated derivatives of many naturally-occurring [56, 66-78] and pharmaceutically interesting [79-83] 3-arylchromones. Its application to the preparation of 5-alkoxy- [47] and 3-alkyl (or araklyl)-chromone-2-carboxylic adds and esters has been described [50, 84-90]. 

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