Keto esters hydrogenation reactions

The Claisen condensation is one method of synthesizing (3-dicarbonyl compounds, specifically a (3-keto ester. This reaction begins with an ester and occurs in two steps. In the first step, a strong base, such as sodium ethoxide, removes a hydrogen ion from the carbon atom adjacent to the carbonyl group in the ester. (Resonance stabilizes the anion formed from the ester.) The anion can then attack a second molecule of the ester, which begins a series of mechanistic steps until the anion of the (3-dicarbonyl compound forms, which, in the second reaction step (acidification), gives the product. 

Scheme 1 a The [2 + 2] cycloaddition product of prochiral trans 2-butene with Si dimers of the Si(100) surface leads to chiral adsorbate complexes, b Hydrogenation of prochiral a-keto esters over platinum is a heterogeneously catalyzed reaction leading to chiral alcohols. Using cinchonidin as chiral modifier makes this surface reaction enantioselective. In a similar fashion, TA-modified nickel is a highly enantioselective catalyst for /3-keto ester hydrogenation... 

Alkylation of aldehydes and -keto esters, This reaction can be conducted by use of solid-liquid phase-transfer catalysis using powdered sodium hydroxide as base and benzene as the solvent. Under these conditions aldehydes with only one a -hydrogen, such as isobutyraldehyde, are alkylated in reasonable yield even by less reactive halides (equation I). 

Collier P.J., Goulding T., Iggo J.A. and Whyman R. (1995) Studies of the Pt-cinchona alkaloid catalyst for enantioselective alpha-keto esters hydrogenation, in Jannes G. and Dubois V. (eds.). Chiral Reactions in Heterogeneous Catalysis, Plenum Press, N.Y. p. 105-110. 

Alternatively, the surface of a metal can be modified with an enantiomerically pure additive. For example, in 1956 palladium metal/silk fibroin was used for the hydrogenation of alkenes with moderate enantioselectivity. However, most success with modified metal siufaces has been achieved in the hydrogenation of ketones. The reduction of 3-keto esters with a Raney nickel/tartaric acid/sodium bromide catalyst provides good enantioselectivities. For example, P-keto ester (3.108) affords the P-hydroxy ester (3.109). Platinum metal modified with cinchona alkaloids has been successfully used with a-keto esters. The reaction yields product with up to 90% ee in the reduction of a-keto ester (3.110). ... 

As we learned earlier in this section, esters that have only one a hydrogen cannot be converted to j8-keto esters by sodium ethoxide. However, they can be converted to j8-keto esters by reactions that use very strong bases such as lithium diisopropylamide (LDA) (Section 18.4). The strong base converts the ester to its enolate ion in nearly quantitative yield. This allows us to acylate the enolate ion by treating it with an acyl chloride or an ester. An example of this technique using LDA is shown here ... 

The formation of ethyl acetoacetate is an example of a general reaction knowu as the acetoacetlc ester condensation in which an ester having hydrogen on the a-carbon atom condenses with a second molecule of the same ester or with another ester (which may or may not have hydrogen on the a-carbon atom) in the presence of a basic catalyst (sodium, sodium ethoxide, sodamide, sodium triphenylmethide) to form a p-keto-ester. The mechanism of the reaction may be illustrated by the condensation of ethyl acetate with another molecule of ethyl acetate by means of sodium ethoxide. ... 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

The aryl- and heteroarylfluorosilanes 541 can be used for the preparation of the unsymmetrical ketones 542[400], Carbonylation of aryl triflate with the siloxycyclopropane 543 affords the 7-keto ester 545. In this reaction, transme-tallation of the siloxycyclopropane 543 with acylpalladium and ring opening generate Pd homoenolate as an intermediate 544 without undergoing elimination of/3-hydrogen[401],... 

Active methylene or methine compounds, to which two EWGs such as carbonyl, alko.xycarbonyl, formyl, cyano, nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59]. 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is earned out with a /3-keto ester, /9-diketone, malonate, Q-formyl ketones, a-cyano and Q-nitro esters, cya noacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

The reaction between perfluoraarylmagnesium halides and esters of dicar-boxyltc acids gives, besides the expected keto esters, secondary alcohols as reduction products [29, 30, 31] (equation 10) Such a reduction is enhanced by higher temperature The hydrogen necessary for reduction comes from the solvent, diethyl ether, which is dehydrogenated to ethyl vinyl ether, which has been identified as a by-product in a similar reaction of perfluoroalkyllithium compound [52]... 

Carboxylic esters 1 that have an a-hydrogen can undergo a condensation reaction upon treatment with a strong base to yield a /3-keto ester 2. This reaction is called the Claisen ester condensation or acetoacetic ester condensation, the corresponding intramolecular reaction is called the Dieckmann condensation ... 

Some workers avoid delay. Pai)adium-on-carbon was used effectively for the reductive amination of ethyl 2-oxo-4-phenyl butanoate with L-alanyl-L-proline in a synthesis of the antihyperlensive, enalapril maleate. SchifTs base formation and reduction were carried out in a single step as Schiff bases of a-amino acids and esters are known to be susceptible to racemization. To a solution of 4,54 g ethyl 2-oxO 4-phenylbutanoate and 1.86 g L-alanyl-L-proline was added 16 g 4A molecular sieve and 1.0 g 10% Pd-on-C The mixture was hydrogenated for 15 hr at room temperature and 40 psig H2. Excess a-keto ester was required as reduction to the a-hydroxy ester was a serious side reaction. The yield was 77% with a diastereomeric ratio of 62 38 (SSS RSS)((55). 

Esters, like aldehydes and ketones, are weakly acidic. When an ester with an a- hydrogen is treated with 1 equivalent of a base such as sodium ethoxide, a reversible carbonyl condensation reaction occurs to yield a /3-keto ester. For example, ethyl acetate yields ethyl acetoacetate on base treatment. This reaction between two ester molecules is known as the Claisen condensation reaction. (We ll use ethyl esters, abbreviated "Et," for consistency, but other esters will also work.)... 

If the starting ester has more than one acidic a hydrogen, the product /3-keto ester has a highly acidic, doubly activated hydrogen atom that can be abstracted by base. This deprotonation of the product requires that a full equivalent of base rather than a catalytic amount be used in the reaction. Furthermore, the... 

The mixed Claisen condensation of two different esters is similar to the mixed aldol condensation of two different aldehydes or ketones (Section 23.5). Mixed Claisen reactions are successful only when one of the two ester components has no a hydrogens and thus can t form an enolate ion. For example, ethyl benzoate and ethyl formate can t form enolate ions and thus can t serve as donors. They can, however, act as the electrophilic acceptor components in reactions with other ester anions to give mixed /3-keto ester products. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

Intermediate 37 can be transformed into ( )-thienamycin [( )-1)] through a sequence of reactions nearly identical to that presented in Scheme 3 (see 22— 1). Thus, exposure of /(-keto ester 37 to tosyl azide and triethylamine results in the facile formation of pure, crystalline diazo keto ester 4 in 65 % yield from 36 (see Scheme 5). Rhodium(n) acetate catalyzed decomposition of 4, followed by intramolecular insertion of the resultant carbene 3 into the proximal N-H bond, affords [3.2.0] bicyclic keto ester 2. Without purification, 2 is converted into enol phosphate 42 and thence into vinyl sulfide 23 (76% yield from 4).18 Finally, catalytic hydrogenation of 23 proceeds smoothly (90%) to afford ( )-thienamycin... 

Scheme 28. Examples of Ru-catalyzed asymmetric hydrogenation reactions of /i-keto esters...

The principles of the SE were applied for two enantioselective hydrogenation reactions (i) hydrogenation of P-keto esters over Ni-tartrate and (ii) hydrogenation of a-keto esters over cinchona-Pt/Al203 catalysts. In this respect the tartaric acid - P-keto ester system gave a negative result. Neither the substrate nor the modifier have bulky substituents required for SE. 

CDj a The simplified reaction scheme for the enantioselective hydrogenation of a-keto esters over cinchona-Pt/Al203 catalyst can be written as follows ... 

More recently, these authors have reported the synthesis of a new thiophene-based analogue of (I ,i )-Me-DuPHOS called UlluPHOS. The facial recognition and enantioselection associated with ruthenium complexes of UlluPHOS and Me-DuPHOS were shown to be similarly high in various hydrogenations of p-keto esters (Scheme 8.32). The most important difference between these two ligands was found by comparing the reaction rates. Indeed, the authors have observed that the use of UlluPHOS considerably increased the activity of the complexes. 

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