Substrate ketoesters

The coupling of arenediazonium compounds 1 to 1,3-dicarbonyl substrates 2 (Z = COR) is known as the Japp-Klingemann reaction As suitable substrates, /3-ketoacids (Z = COOH) and /3-ketoesters (Z = COOR) can be employed. As reaction product an arylhydrazone 4 is obtained. 

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]. 

The first substrate analogue inhibitors of FAAH were reported in 1994. The anandamide analogues prepared represented three elasses of putative transition-state inhibitors a-trifluoromethyl ketones, a-ketoesters and a-ketoamides [62], In the initial sereening studies, it was found that the trifluoromethyl ketone eompounds tested were effeetive inhibitors of AEA hydrolysis. A selected set of a-keto esters also inhibited hydrolysis, while a-keto amides were ineffective. In particular, arachidonyl trifluoromethyl ketone (32), gave almost 100% inhibition of anandamide hydrolysis. A detailed investigation of the structural requirements for FAAH inhibition with a-trifluoromethyl ketones has been carried out by Roger and co-workers [63]. 

Pt/Al2C>3-cinchona alkaloid catalyst system is widely used for enantioselective hydrogenation of different prochiral substrates, such as a-ketoesters [1-2], a,p-diketones, etc. [3-5], It has been shown that in the enantioselective hydrogenation of ethyl pyruvate (Etpy) under certain reaction conditions (low cinchonidine concentration, using toluene as a solvent) achiral tertiary amines (ATAs triethylamine, quinuclidine (Q) and DABCO) as additives increase not only the reaction rate, but the enantioselectivity [6], This observation has been explained by a virtual increase of chiral modifier concentration as a result of the shift in cinchonidine monomer - dimer equilibrium by ATAs [7],... 

Zhu, D., Mukherjee, C., Rozzell, J.D. et al. (2006) A recombinant ketoreductase tool-box. Assessing the substrate selectivity and stereoselectivity toward the reduction of beta-ketoesters. Tetrahedron, 62 (5), 901-905. 

Polymerization of a BINAP derivative (Figure 14) followed by complexation with [ RuC12 (benzene) 2] afforded a catalyst showing high enantioselectivities for the hydrogenation of various substrates such as dehydroaminoacids, ketoesters, olefins, and ketones.135 The catalyst may be re-used four times with negligible loss of enantioselectivity and activity. 

A Knorr-type pyrrole synthesis involving the condensation between a-amino-P-ketoesters and P-ketonitriles provided P-cyanopyrroles <06OPRD899>. The former amine substrates were prepared by reduction of the corresponding a-isonitroso-P-ketoesters with Zn/HOAc. 

The C-H insertion of acetals generates protected forms of /3-ketoesters, as illustrated in Equation (22).83 Effective reactions were possible with aryl, vinyl, and alkynyl ketals, but ketals of saturated aldehydes were not viable substrates. 

A titanium(iv) chloride mediated Baylis-Hillman-type or aldol reaction between a-ketoesters and cyclohex-2-enones has been studied (Equation (13)).77 The steric effect of the R2 substituent is crucial for the reaction pathway since the aldol reaction only proceeds with the unsubstituted cyclohexenone (aldol adduct 71 with R2 = H to a small extent the Baylis-Hillman reaction occurs), whereas with the substituted substrate (R2 = Me) gives exclusively the Baylis-Hillman adduct 72. 

The enantioselective hydrogenation of prochiral substances bearing an activated group, such as an ester, an acid or an amide, is often an important step in the industrial synthesis of fine and pharmaceutical products. In addition to the hydrogenation of /5-ketoesters into optically pure products with Raney nickel modified by tartaric acid [117], the asymmetric reduction of a-ketoesters on heterogeneous platinum catalysts modified by cinchona alkaloids (cinchonidine and cinchonine) was reported for the first time by Orito and coworkers [118-121]. Asymmetric catalysis on solid surfaces remains a very important research area for a better mechanistic understanding of the interaction between the substrate, the modifier and the catalyst [122-125], although excellent results in terms of enantiomeric excesses (up to 97%) have been obtained in the reduction of ethyl pyruvate under optimum reaction conditions with these Pt/cinchona systems [126-128],... 

Carpentier and coworkers studied the asymmetric transfer hydrogenation of /f-keloeslers using chiral ruthenium complexes prepared from [(// -p-cyrriene)-RuC12]2 and chiral aminoalcohols based on norephedrine. During this study, these authors became aware of substrate inhibition when ketoesters carrying 4-halo-substituents were used. It transpired that this was caused by formation of a complex between the substrate and the catalyst [28]. 

The hetero-Diels-Alder reaction between a,p-unsaturatcd ketoesters and nucleophilic alkenes has been described in two concurrent and independent reports (220, 222). As with acylphosphonates, these proved to be excellent substrates for catalyst 269c. The reaction proceeds efficiently in THF at low temperatures providing the cycloadduct in >99% ee at -78°C. Indeed, the impressive selectivity exhibited under these conditions allows the reaction to be conducted at a convenient temperature of 0°C, using the hydrated catalyst 266c in the presence of molecular sieves, Eq. 181. Observed diastereoselectivities... 

Some ketones 70, 72, 73 and 75 gave low yields most likely due to low solubility in aqueous solution and small binding constants of the inclusion complexes. It is important to note that double bonds were not reduced in compounds 68-70 and styrene could be stirred at 50°C for three days in the presence of the catalyst without alkane formation, i.e., the reaction proceeds completely chemoselective. This is also valid for the a- and P-ketoesters 76-79, though for these substrates the enantioselectivities are low (Fig. 23). 

Similar to the case of Suzuki couplings (6.1.2), ally lie alkylations can also be run in neat water as solvent in the presence of surfactants. In addition to the general solubihzation effect, the amphiphiles may also have a specific influence on the reaction rate. For example, the reaction of the P-ketoester substrate on Scheme 6.22 with allyl acetate, catalyzed by [Pd(PPh3)4] was only slightly accelerated by the anionic SDS (1.5 h, 18 % yield), however, the reaction rate dramatically increased in the presence of the cationic CTAB and the neutral Triton X-100 detergents, leading to 74 % and 92% yields in 1.5 h and 5 min ( ), respectively [51]. Several other carbonucleophiles were alkylated in such emulsions with excellent yields. 

Primary and secondary nitroalkanes, and substrates containing terminal em-dinitroaliphatic functionality, have one or more acidic a-protons, a consequence of inductive and resonance effects imposed by the nitro group. As a result, such compounds can behave like carbanions and participate in a number of addition and condensation reactions which are typical of substrates like ketones, aldehydes, and /S-ketoesters. Such reactions are extremely useful for the synthesis of functionalized polynitroaliphatic compounds which find potential use as explosives, energetic oligomers and plasticizers. 

The methylene hydrogens between the two carbonyls are the most acidic, so this is where enolate anion formation occurs. Now follows an Sn2 reaction with the dibromide reagent. It is soon apparent that this sequence of enolate anion formation and Sn2 displacement can be repeated, since the substrate still contains an acidic hydrogen. We soon end up with an alkylated ketoester. 

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). 

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. 

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