Ketones, catalytic condensation with esters

Acyloins were converted to mixtures of stereoisomeric vicinal diols by catalytic hydrogenation over copper chromite [972]. More frequently they were reduced to ketones by zinc (yield 77%) [913, 914], by zinc amalgam (yields 50-60%) [975], by tin (yields 86-92%) [173], or by hydriodic acid by refluxing with 47% hydriodic acid in glacial acetic acid (yields 70-90%) [916], or by treatment with red phosphorus and iodine in carbon disulfide at room temperature (yields 80-90%) [917] Procedure 41, p. 215). Since acyloins are readily accessible by reductive condensation of esters (p. 152) the above reductions provide a very good route to ketones and the best route to macro-cyclic ketones [973]. 

Most C,H-acidic compounds can be condensed with aldehydes or ketones to yield alkenes. Some of these reactions have also been realized on insoluble supports, with either the C,H-acidic (nucleophilic) reactant or the electrophilic reactant linked to the support. Some illustrative examples are listed in Table 5.6. Polystyrene-bound malonic esters or amides, cyanoacetamides, nitroacetic ester [95], and 3-oxo esters undergo Knoevenagel condensation with aromatic or aliphatic aldehydes. Catalytic amounts of piperidine and heating are generally required, although reactive substrates can react at room temperature. 

The ketone (XXVI) was condensed with ethyl bromoacetate in a Reformatsky reaction, and the resulting unsaturated ester (XXXIV) was catalytically reduced and then saponified to give the endo acid (XXXV). Its configuration follows from its mode of formation and is confirmed by its cyclization in the presence of trifiuoroacetic anhydride to the bridge ketone (XXXVI). 

Diesters of malonic acid, as well as other active methylene compounds such as ace-toacetic esters and cyanoacetic esters, condense with aldehydes and ketones in the presence of catalytic amounts of primary or secondary amines or ammonium salts. 

Enolsilylation. a-Bromo ketones and esters are transformed into trichlorosilyl enol ethers by HSiCls and EtsN (catalytic Ph3PO), which condense with ArCHO. The overall process is superior to the Wittig reaction. 

Alkylphosphonate esters. The carbanion generated from dechlorination with BuLi condenses with aldehydes (and some ketones). Catalytic hydrogenation of the (chlorovinyl)phosphonate products affords phosphonates. 

The acyl carbon of readily available amino acids such as alanine can be converted to a ketone moiety by activation of the acid with carbonyl diimidazole (CDI) and then condensation with an enolate, such as the magnesium enolate of malonic acid, mono ethyl ester. In this particular example, N-Boc alanine was converted to 1.206 using this method O Catalytic hydrogenation of the ketone moiety gave the alcohol group in 1.207, and conversion to the chloride and base induced dehydrohalogen-ation gave ethyl 4-(N-Boc amino)pent-2-enoate (7.205). 

The acid moiety of an amino acid can be activated for acyl substitution rather than converted to an aldehyde for acyl addition. Boc-alanine was converted to an acyl imidazole by reaction with carbonyl diimidazole (CDI see chapter two, section 2.4), and then condensed with the magnesium enolate of the mono ethyl ester of malonic acid to give keto-ester 5.9. Subsequent catalytic hydrogenation of the ketone moiety gave ethyl 3-hydroxy-5-(N-Boc amino)penlanoate, 5.10 Once the o... 

Reactions of Thiophen Aldehydes and Ketones.— The Stobbe condensation of some thienylcarbonyl compounds with dimethyl methylsuccinate in the presence of potassium t-butoxide or sodium hydride gave predominantly the ( -half esters of (156), while condensation with dimethyl homophthalate gave predominantly the (Z)-half ester of (157). Thiophen-2-aldehydes were shown to add smoothly to a -unsaturated ketones and nitriles, under the catalytic influence of cyanides, to form (158) and (159), respectively. Thiophen-2-aldehydes have been condensed with aliphatic amines and phenylenediamine to give Schiff bases ... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Carboxylic esters can be treated with ketones to give p-diketones in a reaction that is essentially the same as 10-118. The reaction is so similar that it is sometimes also called the Claisen condensation, though this usage is unfortunate. A fairly strong base, such as sodium amide or sodium hydride, is required. Yields can be increased by the catalytic addition of crown ethers. Esters of formic acid (R H) give P-keto aldehydes. Ethyl carbonate gives P-keto esters. 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

Cyclopropanation, Horner-Wadsworth Emmons Reaction, and Darzens Condensation Although induction in the cyclopropanation of alkenes was reported early, this work was disputed [49]. Other reports of cyclopropanations have yielded, at best, low asymmetric inductions [llh,50]. The first example of a catalytic asymmetric Horner-Wadsworth Emmons reaction, which is promoted by a chiral quaternary ammonium salt, was reported recently by the Shioiri group (Scheme 10.10) [51]. The reaction of the prochiral ketone 74 gives optically active a,P-unsaturated ester 76 with 57% ee. 

The first example of a catalytic asymmetric Horner-Wadsworth-Emmons reaction was recently reported by Arai et al. [78]. It is based on the use of a chiral quaternary ammonium salt as a phase-transfer catalyst, 78, derived from cinchonine. Catalytic amounts (20 mol%) of organocatalyst 78 were initially used in the Homer-Wadsworth-Emmons reaction of ketone 75a with a variety of phospho-nates as a model reaction. The condensation products of type 77 were obtained in widely varying yields (from 15 to 89%) and the enantioselectivity of the product was low to moderate (< 43%). Although yields were usually low for methyl and ethyl phosphonates the best enantioselectivity was observed for these substrates (43 and 38% ee, respectively). In contrast higher yields were obtained with phosphonates with sterically more demanding ester groups, e.g. tert-butyl, but ee values were much lower. An overview of this reaction and the effect of the ester functionality is given in Scheme 13.40. 

Laurone has been prepared by hydrating and decarboxylating decylketene dimer.3 It has also been prepared by distilling calcium laurate 4 by heating lauric acid with phosphorus pent-oxide 5 by heating barium laurate under reduced pressure 6 by the ester condensation of ethyl laurate with sodium ethoxide 7 or of methyl laurate with sodium hydride 8 followed by ketonic hydrolysis by catalytic ketonization of lauric acid over a chromate catalyst 9 or by passing lauric acid over thorium dioxide at 400°.10... 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

Boric acid catalyzes the self-condensation of aldehydes and ketones to produce a,/l-unsaturated enones [6]. The yields are much higher than those reported with other acidic or basic catalysts. Under similar conditions, aldehydes which are not readily susceptible to aldol condensation, dismutate to form esters (Tischenko reaction) [7]. A catalytic amount of boric acid-sulfuric acid mixture has been used to synthesize aryl esters in good yields (Eq. 3) [8] this reaction was unsuccessful when mineral acids or boric acid alone were used. 

The condensation of enolates derived from malonic esters and other active methylene compounds with a,p-unsaturated aldehydes, ketones, esters, or nitriles proceeds exclusively by 1,4-addition. The conjugate addition to a,(3-unsaturated compounds, often called Michael acceptors, is promoted by treatment of the active methylene species with either an excess of a weak base (e.g., Et3N or piperidine) or using a stronger base in catalytic amounts (e.g., 0.1-0.3 equivalents NaH, NaOEt, or r-BuOK). 

A useful modification of the Knorr pyrrole synthesis was developed in the laboratory of J.M. Hamby for the construction of tetrasubstituted pyrroles. The necessary a-amino ketones were prepared from A/-methoxy-A/-methylamides of amino acids (Weinreb amides). These Weinreb amides were prepared by the mixed anhydride method and treated with excess methylmagnesium bromide in ether to afford the corresponding Cbz-protected a-amino ketones in excellent yield. The Cbz group is removed by catalytic hydrogenation in the presence of the active methylene compound (e.g., acetoacetic ester), the catalyst is then filtered and the resulting solution is heated to reflux to bring about the condensation. 

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