Tertiary a-Aryl Carbonyls

Enantioenriched tertiary a-aryl carbonyls represent an important class of organic compounds. They are prevalent structural motifs in many biologically active molecules and pharmaceuticals such as naproxen and clopidogrel. They are also important intermediates in the synthesis of many medicinally important molecules. 

As a result the asymmetric synthesis of compounds possessing this structural motif has received a great deal of attention, particularly in the last decade. 

A number of other asymmetric enolate protonation reactions have been described using chiral proton sources in the synthesis of a-aryl cyclohexanones. These include the stoichiometric use of chiral diols [68] and a-sulfinyl alcohols [69]. Other catalytic approaches involve the use of a BlNAP-AgF complex with MeOH as the achiral proton source, [70] a chiral sulfonamide/achiral sulfonic acid system [71,72] and a cationic BINAP-Au complex which also was extended to acyclic tertiary a-aryl ketones [73]. Enantioenriched 2-aryl-cyclohexanones have also been accessed by oxidative kinetic resolution of secondary alcohols, kinetic resolution of racemic 2-arylcyclohexanones via an asymmetric Bayer-Villiger oxidation [74] and by arylation with diaryhodonium salts and desymmetrisation with a chiral Li-base [75]. 

Despite the number of reports of the asymmetric synthesis of tertiary a-aryl cyclohexanones, there have only been three reports which describe the asymmetric synthesis of tertiary a-aryl cyclopentanones. The first of these was reported by Shi via asymmetric epoxidation of benzylidene cyclobutanes and epoxide rearrangement in a subsequent step [76]. Backvall used a dynamic kinetic resolution of aUyhc alcohols-aUylic substitution-oxidative cleavage sequence to access 2-phenylcyclopentanone [77]. The first direct catalytic asymmetric synthesis of tertiary a-aryl ketones was recently described by Kingsbury using a series of Sc-catalysed diazoalkane-carbonyl homologations with bis/tris oxazohne ligands [78]. 

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A number of approaches have been developed for the catalytic asymmetric synthesis of quaternary a-aryl carbonyl containing compounds. However, the basic conditions employed in the vast majority of the reports to date necessitate the use of basic conditions (e.g. (1), Scheme 4.34). Therefore, these methods are unsuitable for the synthesis of tertiary a-aryl carbonyls due to the acidity of a tertiary a-aiyl carbonyl proton. Excellent progress has been made in recent years in the realisation of a catalytic asymmetric synthesis of tertiary a-aryl carbonyls (Scheme 4.34). 

This method is of quite general applicability and the carbonyl compound may be an aldehyde, a ketone, or an ester. Similarly, the halide may be chloride, bromide, or iodide although yields are generally lower with iodides. Alkyl and aryl halides react with equal facility and the alkyl halide may be primary, secondary, or tertiary. A few examples of the yields obtained with a variety of reagents are given in Table I (the yields quoted are obtained by g.l.c. analysis of the reaction mixture using an internal standard ). 

There has been continued interest in the synthesis of oxazoles from a-diazo carbonyl compounds and nitriles catalyzed by Lewis acids. The BFa-catalyzed reaction of a-diazoacetophenones or methyl p-nitrophenyldiazoacetate with chloroacetonitrile affords 5-aryl-2-chloromethyloxazoles or 2-chloromethyl-5-methoxy-4-(p-nitrophenyl)oxazole, respectively (Equation (19)) <89BCJ618>. The former products react with primary, secondary, and tertiary amines by nucleophilic displacement of the chloride group. Methyl or ethyl isocyanate may be used as the nitrile component to prepare... 

Addition of BujSnH to enynes is regw nyl-1,3-dienes readily available. Csclizati carbonylation is a useful way to access fun enes undergo reactions at both ends u iih allylamines bearing an a>-aryl group Allylic substitutions. Allyl ic carbo ethers, amines, sulfides on exposure ii Pd2(dba)j, and a tertiary phosphine. 

Enantioselective additions of metal aryl species to ketones are more challenging transformations than the use of aldehydes as acceptors. This situation is related not only to the decreased reactivity of ketones as acceptors, but also to the greater difficulty for a Lewis acid to differentiate between the two lone pairs of a ketone carbonyl. An early example of an enantioselective phenyl transfer to aryl-alkyl ketones 23 was reported by Fu in 1998 (Scheme 8.7) [21]. The use of Noyori s dimethylaminoisobomeol (DAIB) Ugand 24 provided tertiary alcohols 25 in moderate to high yields and enantioselectivities. The addition of methanol was found to be necessary in order to form a mixed alkoxy phenyl zinc species which is less reactive than Ph2Zn. 

The sixth chapter of the book was devoted to advances in enantioselective nickel-catalysed a-functionalisation, and to a-alkylation/arylation reactions of carbonyl compounds. A prochiral carbonyl compound can be activated toward electrophilic substitution via the formation of an enol or enolate intermediate, generating a tertiary or quaternary centre at the a-carbon. The use of a non-carbon electrophile leads to heterofunctionalised products, while that of carbon electrophiles affords a-arylated/alkylated carbonyl compounds, and the generation of a new stereogenic centre in these reactions... 

Reduction of amides (Section 22.9) Lithium aluminum hydride reduces the carbonyl group of an amide to a methylene group. Primary, secondary, or tertiary amines may be prepared by proper choice of the starting amide. R and R may be either alkyl or aryl. 

Formation of aldehydes. Aldehydes can be prepared by the carbonylation of halides in the presence of various hydride sources. The carbonylation of aryl and alkenyl iodides and bromides with CO and H (1 1) in aprotic solvents in the presence of tertiary amines affords aldehydes[373,374]. Aryl chlorides, as tricarbonylchromium derivatives, are converted into aldehydes at 130 C[366], Sodium formate can be used as a hydride source to afford aldehydes. Chlorobenzene (514) was carbonylated at 150 °C to give benzaldehyde with CO and sodium formate by using dippp as a ligand[375,376]. 

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