AROMATIC /3-KETOESTERS

Under basic conditions, the o-nitrotoluene (5) undergoes condensation with ethyl oxalate (2) to provide the a-ketoester 6. After hydrolysis of the ester functional group, the nitro moiety in 7 is then reduced to an amino function, which reacts with the carbonyl group to provide the cyclized intermediate 13. Aromatization of 13 by loss of water gives the indole-2-carboxylic acid (9). 

A fully unsaturated tricyclic indole derivative serves as the aromatic moiety for a nonsteroid antiinflammatory agent. Preparation of this compound starts with the Michael addition of the anion from methyl diethylmalonate to cyclohexanone. The product (32) is then hydrolyzed and decarboxylated to give ketoester 33. Fischer condensation with p-chlorophenylhydrazine leads to the indole This is then esterified (35) and dehydrogenated to the carbazole 36. Saponification leads... 

R = Aliphatic, aromatic, X = -OR, -NR2 R = Aromatic Scheme 20 Two step synthesis of pyrazoles from /3-ketoesters... 

Oxa-tetrahydropyridines are interesting intermediates for the preparation of pharmaceuticals and natural product based alkaloid systems. A modified Hantzsch reaction was developed under microwave irradiation for the preparation of 2-oxa-tetrahydropyridines 173 by reaction of Meldrum s acid, a /3-ketoester and an aldehyde, using NH4OAC as the source of ammonia (Scheme 62). Yields ranged from 81 to 91% at temperatures of 100-130 °C depending on the substrate (the aldehyde) employed. All the products obtained have the same structure except for the aromatic substituent in position 4 [109]. 

In the Diels-Alder reaction with inverse electron demand, the overlap of the LUMO of the 1-oxa-l,3-butadiene with the HOMO of the dienophile is dominant. Since the electron-withdrawing group at the oxabutadiene at the 3-position lowers its LUMO dramatically, the cycloaddition as well as the condensation usually take place at room or slightly elevated temperature. There is actually no restriction for the aldehydes. Thus, aromatic, heteroaromatic, saturated aliphatic and unsaturated aliphatic aldehydes may be used. For example, a-oxocarbocylic esters or 1,2-dike-tones for instance have been employed as ketones. Furthermore, 1,3-dicarbonyl compounds cyclic and acyclic substances such as Meldmm s acid, barbituric acid and derivates, coumarins, any type of cycloalkane-1,3-dione, (1-ketoesters, and 1,3-diones as well as their phosphorus, nitrogen and sulfur analogues, can also be ap-... 

The carbonyl reductase from Candida magnoliae catalyzed the enantioselective reduction of a diversity of ketones, including aliphatic and aromatic ketones and a- and /3-ketoesters (Figure 7.17), to anti-Prelog configurated alcohols in excellent optical purity (99% ee or higher) [56]. 

A very impressive example of the synthetic utility of this chemistry is the one-pot enantioselective double G-H activation reaction of 86 to generate chiral spiran 87 (Equation (73)).172 In this case, the phthalimide catalyst Rh2(enantiotopically selective aromatic C-H insertions of diazo ketoesters (Equation (74)).216 Moreover, dirhodium(n) tetrakisIA-tetrafluorophthaloyl- )-/ /-leucinate], Rh2(hydrogen atoms of the parent dirhodium(n) complex are substituted by fluorine atoms, dramatically enhances the reactivity and enantioselectivity (up to 97% ee). Catalysis... 

Titanium-mediated pinacol coupling reactions have been reviewed until 2000.80 81 Since then, various intermole-cular pinacol couplings have been reported with aldehydes, - ketones, a-ketoesters, and imines, as well as asymmetric versions thereof.101-104 Scheme 29 shows one example of an asymmetric pinacol coupling of aromatic aldehydes, promoted and catalyzed by the new chiral titanium complex (A)-75, that has been developed by Riant and co-workers.101 Yields for pinacol products 76 are generally high. Under catalytic conditions, ee is moderate (up to 63%), while stoichiometric conditions allow to obtain up to 91% ee. 

A double tethered Biginelli reaction was carried out on the simple five-membered urea aldehyde 305 that reacted with the aliphatic and aromatic bis-ketoesters 306 and 307 giving compounds 308 and 309, respectively, in good yield, albeit with a diasteromeric ratio of 1 3. A series of different polycyclic bis-guanidines resembling betzelladine alkaloids were prepared <2003OL4485>. 

This chemistry was extended to a catalytic enantioselective alkenylation and phenylation of aldehydes and a-ketoesters. Using CuF-DTBM-SEGPHOS complex, products were obtained with excellent enantioselectivity from a wide range of aldehydes including aromatic and aliphatic aldehdyes, [Eq. (13.26)]. Previously catalytic enantioselective vinylation and phenylation are restricted using the corresponding zinc reagents. The active nucleophile is proposed to be an alkenyl or phenyl copper, based on NMR studies. The chiral CuF catalyst can also be applied to a catalytic enantioselective aldol reaction to ketones... 

Using optimal bifunctional catalyst 166, the reaction scope was expanded to aromatic, heteroaromatic, and aliphatic nitro-olefms. Catalyst 166 also promoted the addition of a p-phenyl nitro-olefm to a-CHj-P-ketoester, achieving an asymmetric quaternary center in high yield and high enantiomeric ratio (Scheme 48). 

More specifically, 3,5-di-ferf-butylphenyl substitution on the 3,3 -position of the binaphthol backbone (260) provided overall best yields and selectivities. Using catalyst 260, the authors expanded the scope of substrates to include aliphatic and aromatic nitro-alkenes, and a-substituted P-ketoesters, while maintaining good yields and enantiomeric ratios (Scheme 71). 

In addition, iodine snccessfnlly catalyzed the electrophilic snbstitntion reaction of indoles with aldehydes and ketones to bis(indonyl)methanes [225], the deprotection of aromatic acetates [226], esterifications [227], transesterifications [227], the chemoselective thioacetalization of carbon functions [228], the addition of mercaptans to a,P-nnsatnrated carboxylic acids [229], the imino-Diels-Alder reaction [230], the synthesis of iV-Boc protected amines [231], the preparation of alkynyl sngars from D-glycals [232], the preparation of methyl bisnlfate [233], and the synthesis of P-acetamido ketones from aromatic aldehydes, enolizable ketones or ketoesters and acetonitrile [234],... 

Our own group is also involved in the development of domino multicomponent reactions for the synthesis of heterocycles of both pharmacologic and synthetic interest [156]. In particular, we recently reported a totally regioselective and metal-free Michael addition-initiated three-component substrate directed route to polysubstituted pyridines from 1,3-dicarbonyls. Thus, the direct condensation of 1,3-diketones, (3-ketoesters, or p-ketoamides with a,p-unsaturated aldehydes or ketones with a synthetic equivalent of ammonia, under heterogeneous catalysis by 4 A molecular sieves, provided the desired heterocycles after in situ oxidation (Scheme 56) [157]. A mechanistic study demonstrated that the first step of the sequence was a molecular sieves-promoted Michael addition between the 1,3-dicarbonyl and the cx,p-unsaturated carbonyl compound. The corresponding 1,5-dicarbonyl adduct then reacts with the ammonia source leading to a DHP derivative, which is spontaneously converted to the aromatized product. 

KETENE, feef-butylcyano-, 55, 32 37, 38 Ketene 1 1-dimethylpropylcyano-, 55, 38 7-KETOESTERS, 58, 79, 81, 82 7-KETOESTERS TO PREPARE CYCLIC DIKETONES, 58, 83 KETONE terf-butyl phenyl, 55, 122 Ketone, methyl ethyl- 55, 25 Ketone, methyl vinyl, 56, 36 KETONES, acetylenic, 55, 52 Ketones, alkylation of, 56, 52 KETONFS aromatic, aromatic hydrocarbons from 55, 7... 

Haddadin and Issidorides first reported an elegant method for the synthesis of quinoxaline 1,4-dioxides (47) from the reaction of benzofurazan 1-oxide (46) and an enamine or an active methylene compound, such as a /J-diketone or a /J-ketoester, in the presence of base.46 47 Quinoxaline 1,4-dioxide formation formally involves loss of secondary amine in the enamine reaction and loss of water when an active methylene compound of the type R CH2CORJ is used. This reaction is now commonly referred to as the Beirut reaction. The isolation of the dihydroquinoxaline 1,4-dioxide 48 from the reaction of 46 and NJV-dimethylisobutenylamine (Me2C=CHNMe2), which is unable to aromatize by amine loss, suggests that 2,3-dihydroquinoxalines are likely intermediates in all these reactions.48... 

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